IJO International Journal of Oncology 1019-6439 1791-2423 D.A. Spandidos 10.3892/ijo.2023.5510 ijo-62-5-05510 Articles Research progress on PRMTs involved in epigenetic modification and tumour signalling pathway regulation (Review) WuKailiang NiuChen LiuHanjiao FuLi National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Hexi, Tianjin 300060, P.R. China Correspondence to: Dr Li Fu, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, 1 West Huanhu Road, Tiyuan Bei, Hexi, Tianjin 300060, P.R. China, E-mail: fuli@tmu.edu.cn 05 2023 05 04 2023 62 5 62 20 12 2022 20 03 2023 Copyright: © Wu et al. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Posttranslational modification (PTM) of proteins is essential for increasing protein diversity and maintaining cellular homeostasis, but uncontrolled modification may lead to tumorigenesis. Arginine methylation is a tumorigenesis-related PTM that affects protein function through protein-protein and protein-nucleic acid interactions. Protein arginine methyltransferases (PRMTs) have vital roles in signalling pathways of tumour-intrinsic and tumour-extrinsic microenvironments. The present review summarizes the modifications and functions of PRMTs in histone methylation and nonhistone methylation, their roles in RNA splicing and DNA damage repair and the currently known functions in tumour metabolism and immunotherapy. In conclusion, this article reviews the latest research progress on the role of PRMTs in tumour signal transduction, providing a theoretical basis for clinical diagnosis and treatment. Targeting PRMTs is expected to provide new directions for tumour therapy.

 arginine methyltransferase epigenetic modification signalling pathway tumour metabolism immunotherapy National Natural Science Foundation of China 81672637 81872164 82173344 This study was supported by grants from the National Natural Science Foundation of China (grant nos. 81672637, 81872164 and 82173344). 1. Introduction

Posttranslational modification (PTM) is critical for protein diversity (1). Modification of proteins at one or more sites may determine protein conformation, subcellular localization, type of interacting protein, and protein stability and activity. The PTM process is catalysed by a variety of enzymes, including enzymes involved in phosphorylation, acetylation, ubiquitination, methylation and hydroxylation; conversely, the process may be reversed by enzymes that antagonize these processes, such as phosphatases, deubiquitinases, deacetylases and demethylases (1).

Protein arginine methylation is a common PTM catalysed by protein arginine methyltransferases (PRMTs) (2). In 1967, Paik and Kim (3) first discovered methylated arginine in a nuclear protein of calf thymocytes. The first member of the PRMT family, PRMT1, was identified in 1996, followed by other members (4). Protein arginine methylation has a role in the maintenance of key cellular processes, such as tissue homeostasis and disease phenotype (2).

 2. Classification, structure and function of PRMTs

Based on the number and position of methyl groups on the ω-guanidino nitrogen atom of the protein arginine, arginine methylation modification may be divided into ω-NG-monomethylarginine (MMA), ω-NG,NG-asymmetric dimethylarginine (ADMA) and ω-NG,N'G-symmetric dimethylarginine (SDMA). The process by which PRMTs methylate arginine to produce MMA, ADMA and SDMA is provided in Fig. 1. Among them, type I PRMTs include PRMT1-4, -6 and -8, which methylate MMA and ADMA; type II PRMTs include PRMT5 and -9, which methylate MMA and SDMA; and type III PRMTs include PRMT7, which methylates MMA (5). The protein structure, modulation function and chromosomal location of each member of the PRMTs are provided in Fig. 2.

Arginine is a basic amino acid with a positively charged guanidine group containing five potential hydrogen bond donors, which may interact with negatively charged molecules (6). PRMTs transfer the methyl group from S-adenosine methionine (SAM) to the guanidino group of arginine in protein substrates, resulting in S-adenosyl homocysteine and methylated proteins. After methylation of arginine residues, the distance between side chains increases and the molecular configuration changes. At the same time, the addition of methyl groups reduces the number of potential hydrogen bond donors, resulting in enhanced hydrophobicity of methylated arginine, which in turn affects intramolecular and intermolecular interactions, such as protein-to-protein, protein-to-nucleic acid, as well as protein structure and stability, ultimately affecting the biological function of the modified protein (7).

PRMT1 is the most widely studied PRMT enzyme due to its powerful methyl transfer function, accounting for >85% of all modifications of PRMTs (8). The residues M48, E100, E144, E153, M155 and H293 on the active site of PRMT1 are critical for substrate and cofactor interactions (9). Mutations in these active sites weaken or result in the loss of the catalytic activity of PRMT1, leading to ADMA synthesis disorders (10). The interaction between PRMT2 and RB downregulates the activity of E2F through multiple mechanisms, including histone methylation, transcription factor (TF) methylation and RNA splicing (11). PRMT3 is localised in the cytoplasm and its protein structure includes a catalytic core and a zinc finger domain. Of note, zinc finger domains not only help to recognise RNA substrates but also regulate catalytic activity by recruiting interacting proteins (12). PRMT4, also known as coactivator-associated arginine methyltransferase 1 (CARM1), is mainly located in the nucleus and normally promotes transcription. CARM1 consists of a unique N-terminal EVH1 domain (residues 28-140) that binds to a proline-rich sequence that is essential for substrate recognition and catalytic activity (13). PRMT5 is a major type II PRMT consisting of four domains: An N-terminal TIM-barrel domain, an intermediate Rossmann fold, a C-terminal β-barrel subunit and a dimerization arm (14). The conserved F379 residue of PRMT5 methylates the production of SDMA. The F379M mutation not only increased the methylation activity of PRMT5 but also altered product specificity by generating SDMA and ADMA of H4R3. By contrast, both F379G and F379A mutations significantly reduced PRMT5 activity (14). PRMT6, a signature tag for epigenetic transcriptional repression, specifically methylates ADMA of histone H3 (15). PRMT7 is the only type III PRMT, and compared with other types of PRMTs, the protein structure of PRMT7 includes a narrower substrate-binding site, which may lead to catalytic production of MMA (16). PRMT8 is significantly and specifically highly expressed in brain and neuronal tissues. The N-terminal region of PRMT8 is able to bind to the plasma membrane, and there is a substrate binding site in the middle, which is crucial for PRMT8 methylation activity (17). PRMT9 is a recently identified type II PRMT that includes MTase domains and forms a pseudodimer for substrate binding (18).

 3. Arginine methylation of histones and nonhistones Histone methylation and transcriptional regulation

Arginine methylation of histone tails is an epigenetic modification catalysed by PRMTs and regulates gene expression. PRMTs may methylate H2AR3, H2AR29, H3R2, H3R8, H3R17/26/42, H4R3 and H4R17/19, as presented in Fig. 3. Structural analysis indicated that electrostatic interactions have a mechanistic role in the process of substrate methylation catalysed by PRMTs. It has been indicated that PRMT1, -3, -5 and -8 preferentially methylate histone H4, while PRMT4/CARM1 preferentially methylates histone H3 (19). The detailed functions of the PRMT-methylated histones H2A, H3 and H4 are presented in Table I.

PRMT5-7 are able to methylate H2A. Since the first five residues of H2A and H4 are identical, it is likely that most of the methylation of H4R3 also applies to H2AR3 (20). A systematic analysis of the H2A methylation status revealed that H2AR29me2 was specifically enriched in genes inhibited by PRMT6, suggesting that H2AR29me2 is involved in transcriptional repression (21). The haemagglutinin-PRMT5 complex was also able to monomethylate and symmetrically dimethylate bovine histone H2A (22). Chromatin immunoprecipitation revealed that PRMT7 dimethylates H2AR3 and H4R3 and is enriched at target DNA repair genes in parental cells (23). Studies have indicated that PRMTs are able to methylate H2A and mainly take part in transcriptional repression, but the underlying regulatory mechanism remains to be elucidated.

H3 methylation exerts transcriptional activation or transcriptional inhibition by PRMT2, CARM1 and PRMT5-7. For instance, PRMT2 is responsible for generating H3R8me2a. H3R8me2a enrichment at the BCL2 promoter may increase its accessibility to STAT3, promoting Bcl2 gene expression (24). PRMT2 acts as a transcriptional coactivator for oncogenic gene expression programs in glioblastoma multiforme (GBM) pathogenesis. PRMT2-mediated H3R8me2a enrichment at promoters and enhancers is closely associated with known active histone marks and is required for the maintenance of target gene expression (25). CARM1 may methylate H3R17, H3R26 and H3R42 and is recognised by tudor domain containing 3 to function as a coactivator (26). It is necessary that PRMT5 accumulation activates H3R2me1/me2s and recruitment of the WD repeat domain 5 (WDR5)/mixed linage leukemia (MLL) complex to promote H3K4me3, which in turn activates transcription (27-30). Recruitment of PRMT5 to the forkhead box (FOX)P1 promoter may increase H3R2me2s and H3K4me3 (29). The potential interaction of PRMT5-mediated H3R2me1 with MLL complexes (absent, small, or homologous 2 and WDR5) may activate the expression of metastasis-related genes, such as vimentin, snail family transcriptional repressor 1, snail family transcriptional repressor 2 and cadherin 2 (28). Genotoxic stress induces interactions among β-catenin, ATM phosphorylated Jun isomerization protein 2 and PRMT5, promoting redox-related gene transcription. During this process, PRMT5-mediated recruitment of H3R2me1/H3R2me2s to the WDR5/MLL complex leads to transcriptional activation of H3K4me3 and redox-related genes (30). H3R2me2a acts as a repressive mark that antagonises H3K4me3, but H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and is present in euchromatic regions (31). Profiling of H3-tail interactors indicated that H3R2me2s excludes binding of RBBP7, a central component of the co-repressor complexes SIN3 transcription regulator family member A, nucleosome remodeling and deacetylase and polycomb repressive complex 2. Conversely, H3R2me2s may enhance binding of WDR5, which is a common component of the coactivator complexes MLL, nuclear localization signals 1, Ada two-A containing, SET-domain-containing 1A and SET-domain-containing 1B (31). PRMT6-mediated H3R2me2a inhibits transcription by preventing H3K4me3 readers from binding (32). Of note, H3R8me2s and H4R3me2s are mainly considered repressive markers, but they have also been implicated in the transcriptional activation of certain genes, such as fibroblast growth factor receptor (FGFR)3 and eukaryotic initiation factor 4E expression in colorectal cancer (33) and androgen receptor expression in prostate cancer (34). Overall, for the regulation of H3 methylation, the symmetric arginine dimethylation of H3 generally has a role of transcriptional activation, while the asymmetric arginine dimethylation frequently has a role in transcriptional inhibition.

The methylation of H4 also has a key role in regulating the activation and repression of transcription. For instance, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4, the ATPase subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodelling complex, acts as a binder for PRMT1 to methylate H4R3me2a and upregulate epidermal growth factor receptor (EGFR) in colorectal cancer (35). PRMT5-mediated H4R3me2s have been found on promoters of tumour suppressor and cyclin-dependent kinase (CDK) suppressor genes, which silence cancer-cell proliferation (36,37). Menin (MEN1) has an essential role in both repressing and activating gene expression. In MEN1-excised cells, the levels of both PRMT5 binding and H4R3m2s were decreased at the GLI1 promoter (38). MEN1 is a crucial factor for binding of the Sonic Hedgehog ligand to its receptor Patched 1 and subsequent activation of the Hedgehog signalling pathway. Of note, MEN1 mutants have reduced binding to PRMT5 and fail to impart the repressive H4R3m2s mark at the growth arrest specific 1 promoter, resulting in its elevated expression (38,39). Pharmacologic inhibition of Hedgehog signalling significantly reduces the proliferation of insulinoma cells and promotes the expression of Hedgehog signalling targets (39). Zinc finger E-box binding homeobox 1 (ZEB1), a zinc finger TF, is a key factor for epithelial to mesenchymal transition (EMT) (40). PRMT1 impacted the EMT process by mediating the asymmetric dimethylation of H4R3me2as at the ZEB1 promoter to activate its transcription, indicating the essential roles of this epigenetic control in EMT (41). Otherwise, exogenous TGFβ promotes EMT through PRMT5-MEP50 catalysing arginine monomethylation and dimethylation (42). PHD finger protein 1 (PHF1) recognizes H4R3me2s and recruits CUL4Bring E3 ligase through PHF to form a complex, silencing the expression of E-cad and FBXW7 to promote cell growth and migration (43). In addition, in 293 cells, overexpression of PRMT3 may increase the level of H4R3me2a, but the specific mechanism remains to be clarified (44). In conclusion, these findings reveal a novel link between PRMTs and H4, whereby PRMTs epigenetically regulate tumour signalling pathways, revealing them as targets for treating tumours.

Dynamic crosstalk between different histone modification types may affect gene expression. PRMT7 methylates H4R17me1 and allosterically enhances H4R3me2 of PRMT5, which in turn inhibits subsequent H3K4me3, H3Ac and H4Ac (45). Deacetylation of H3K9 by H3R8me2s is a transcriptional repression marker (46), whereas H4R3me2s is associated with H4K5 acetylation and may serve as a transcriptional activation marker (47). Of note, an increasing number of studies have demonstrated the existence of nonlinear crosstalk between different histone modification types, leading to the diversity of protein functions.

PRMTs may also affect protein tail modification by targeting microRNA (miRNA/miR) and regulating tumour gene expression. PRMT5 repressed the transcription of the miR-99 family by symmetrical dimethylation of H4R3, which increased FGFR3 expression and in turn activated Erk1/2 and Akt, leading to cell growth and metastasis in lung cancer (48). PRMT5 knockdown results in miR33b, miR96 and miR503 derepression through loss of repressive complex recruitment targeting miRNA promoters. PRMT5 is overexpressed in B-cell lymphoma and promotes the binding of miR33b, miR96 and miR503 to the 3'-untranslated region of cyclin D1 and c-MYC mRNAs, indirectly leading to enhanced cyclin D1 and c-MYC expression, which reinforces the relevance of PRMT5 in promoting lymphoma cell growth and survival (49).

 Methylation of nonhistones

According to the function of non-histones after methylation, PRMTs may be divided into five types, including TFs, RNA-binding proteins (RBPs), DNA damage repair proteins, RNA splicing proteins and functional proteins in cell signalling pathways. The detailed functions of PRMT-methylated nonhistones are provided in Table II.

TFs may combine with RNA polymerase to form a transcription initiation complex, which jointly participates in the process of transcription initiation. E2F-1 may regulate transcription in a methylation-dependent manner (50). PRMT5 and -1 methylate E2F-1 to generate functionally opposite effects. The DNA damage response (DDR) induces E2F-1 methylation by PRMT1, increases E2F-1 expression levels and activates apoptotic gene transcription. Conversely, PRMT5 methylation of E2F-1 is recognised by Tudor domain protein, p100/tudor-SN (TSN), which reduces the E2F-1 half-life and increases cell viability. During cell cycle progression, the binding of E2F-1 to cyclin A masks the PRMT1 methylation of E2F-1, thereby inhibiting apoptosis (50). Sterol regulatory element binding protein 1 (SREBP1) is a TF regulated for de novo fatty acid synthesis. PRMT5 methylation of SREBP1 prevents its phosphorylation by glycogen synthase kinase (GSK)3β, but it is subsequently ubiquitinated by F-box and WD repeat domain containing 7 (FBXW7), increasing adipogenesis and promoting tumour growth in hepatocellular carcinoma (HCC) (51). BCL6 is a transcriptional repressor and master regulator of normal germinal centre (GC) formation and GC-derived B-cell lymphomas. PRMT5 methylation of BCL6 at R305 downregulates the activity of BCL6 target genes, inhibiting the growth of diffuse large B-cell lymphoma (52).

ICP27 is an RBP that has a crucial role in the gene expression and replication of herpes simplex virus type 1 (HSV-1) (53). Methylation of ICP27 at residues R138, R148 and R150 by PRMT1 is responsible for the formation of ICP27 nuclear foci, RNA-binding affinity and SRPK interaction. Hypomethylation of ICP27 may significantly inhibit HSV-1 replication, suggesting that PRMT inhibitors have an important role in HSV-2 therapy (53). RNA and transporters compete for binding to nuclear poly(A)-binding protein 1 (PABPN1), but methylation of PABPN1 at R289 reduces the binding capacity between PABPN1 and transporters by ~10-fold, resulting in promotion of the PABPN1-RNA interaction (54). Although eIF4A1 shares >80% sequence similarity with eIF4A2 and -3, only residue R368 of eIF4A1 protein is selectively methylated by PRMT1, whereas other eIF4A isotypes are not (55).

Phosphorylation and ubiquitination are key components of the DDR and arginine methylation is no exception. Deficiency of PRMT1 and PRMT5 leads to spontaneous DNA damage, checkpoint defects and genomic instability in mouse embryonic fibroblasts (56,57). PRMT1 is involved in the methylation of DNA repair proteins, including meiotic recombination 11 (MRE11), p53 binding protein 1, heterogeneous nuclear ribonucleoprotein U like 1, breast cancer 1 (BRCA1) and Separase, which ensure the maintenance of genome stability through homologous recombination (HR) repair and nonhomologous end-joining (NHEJ) (2,58). MRE11 is an essential component of the MRE11-RAD50-NBS1 (MRN) complex that activates the DNA repair pathway. Although methylation of MRE11 does not regulate MRN complex formation, it anchors MRE11 to double-strand breaks (DSBs), preventing nucleases from activating DNA repair. In addition, the TF growth factor independent 1 interacts with PRMT1 and promotes MRE11 methylation (59). Furthermore, CARM1 promotes mitotic arrest deficient 2 like 2 (MAD2L2) silencing by driving the switch from the SWI/SNF complex to EZH2 by methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor-treated HR-proficient cells (60). PRMT5-deficient HeLa cells are sensitive to radiotherapy and accumulate DNA damage (61). Stress-responsive activator of p300 may be recruited to the p53 complex in the DDR, which recruits PRMT5 and promotes methylation of the p53 oligomerization domain to reduce oligomerization and increase nuclear retention (62), while increasing target expression of p21 and p53-up-regulated modulator of apoptosis (63).

Upregulation of key DNA repair genes is the main mechanism of chemotherapy and radiation therapy resistance in tumour cells (64). PRMT5 may promote the survival of tumour cells in the context of genetic damage; therefore, the combination of PRMT5 inhibitors and chemotherapy may be a new strategy to treat cancer resistance. In patients with BRCA1-mutated breast cancer, the HR repair pathway is missing, so the cells rely mainly on PARP-mediated DSB repair. Therefore, Olaparib treatment is effective (65). However, the majority of patients with triple-negative breast cancer (TNBC) do not have BRCA1 mutations and targeting PRMT5 inhibition is similar to HR deficiency in BRCA1 mutations; therefore, targeting PRMT5 inhibition is beneficial for improving patient outcomes (66). Regulator of chromosome condensation 1 (RCC1), as a guanylate exchange factor of RAN, localises in the nucleus and binds to chromatin to regulate DNA damage repair. The methylation of RCC1 at R214 by PRMT6 is necessary for RCC1 to bind to chromatin and activate RAN (67). Inhibition of PRMT6 reduces the tumorigenicity of the cells in GBM and improves the effects of radiation therapy on GBM growth in mice (67).

Interactions between different posttranslational modifications are critical for the DNA damage response. Arginine methylation has an essential role in maintaining genome stability, and arginine methylation and ubiquitination crosstalk control DNA end resection and HR repair (68). Mass spectrometry analysis of PRMT1-interacting proteins revealed that ubiquitin specific peptidase 11 (USP11) has a key role in the early stage of DSB repair by regulating the activity of the PRMT1-MRE11 pathway. USP11 is a substrate of PRMT1 and methylation of USP11 promotes DNA end resection and DSB repair of DNA through HR. PRMT1 is also a ubiquitinated protein that acts as a target of de-ubiquitination to regulate the binding and methylation of PRMT1 to MRE11 (68).

RNA splicing is critical for regulating tumour phenotypes (69,70). Therefore, splicing factors must be tightly controlled genetically and epigenetically to ensure splicing fidelity. It is also important to note that protein arginine methylation usually occurs on the splicing component and that RBPs are required for pre-RNA splicing (71,72). In addition, proteome-wide analysis revealed that the enrichment of arginine-methylated proteins was associated with the control of RNA splicing, trafficking and degradation (73,74). Serine and arginine rich splicing factor 1 (SRSF1) is the substrate and effector of PRMT5 (73,75). Knockdown of PRMT5 resulted in differential binding of SRSF1 to alternative pre-mRNA splicing targets, leading to a decrease in the interaction of SRSF1 with other proteins (73). PRMT5 regulates methylation of the RGG/RG motif in RNA-binding motif protein X and forms a higher-order complex with SRSF1, and splicing generates the short isoform of MDM4 (75). PRMT5 knockdown or inhibition induces aberrant MDM4 splicing, which initiates p53-mediated cell cycle- and apoptosis-related genes, finally promoting tumour growth (76). Furthermore, activation of PRMT5 is critical for sensitivity to CDK4/6 inhibitors, and regulation of the PRMT5-MDM4 axis by palbociclib leads to loss of drug resistance in melanoma (77). By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and delays the emergence of resistance. Tat interactive protein 60kDa (TIP60)/lysine acetyltransferase 5 (KAT5) is a histone lysine acetyltransferase that drives the HR of DNA and is regulated by PRMT5-mediated alternative splicing. In response to DNA damage, PRMT5 promotes alternative splicing of the pre-mRNA of TIP60/KAT to the TIP60a isoform (with high H4 lysine acetylase activity), thereby ensuring HR repair of DNA and maintaining genome integrity (57). In addition to PRMT5 methylation altering transcriptional activity, E2F1 is also involved in alternative splicing after PRMT5 methylation. Methylation of E2F1 promotes the recruitment of p100/TSN and small nuclear ribonucleoprotein, which regulates alternative splicing of E2F1 targets (78). PRMT9 is present in the splicing factor (SF)3B2 and -4 complex and methylates SF3B2. Methylated SF3B2 is recognised by the SMN Tudor domain and has an important role in maintaining splicing fidelity (79).

Methylation of arginine-specific proteins may modify the structure or activity of the protein, alter the interaction between specific molecules and then affect tumour cell signalling pathways. Recent cancer-related studies on the role of PRMTs are summarized in Table III. In TNBC, PRMT1 regulates the EGFR and the Wnt signalling pathways (80). Type I PRMT inhibitors decrease breast cancer cell proliferation and have anti-tumour activity. These inhibitors display synergistic interactions with certain chemotherapies used to treat TNBC, as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC (80). Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer-cell growth inhibition when combined with GSK3368715, which is a potent and reversible type I PRMT inhibitor (81). Of note, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and is associated with sensitivity to GSK3368715. Overall, the MTAP status may serve as a biomarker for patient selection (81). NF-κB has an important role in tumorigenesis and PRMT5 activates NF-κB through methylation of the p65 subunit (82). Although TNFα-induced intracellular signalling pathways have been well studied, the TRAIL signalling pathway remains to be fully elucidated. PRMT5, a novel TRAIL receptor-binding protein, contributes to TRAIL-induced activation of inhibitor of κB kinase (IKK) and NF-κB, leading to induction of several NF-κB target genes (83). PRMT5 methylation of TRIM21 induces selective autophagy, which inhibits TRIM21-dependent monoubiquitination and degradation of IKKβ and activates the NF-κB signalling pathway. Thus, PRMT5 inhibition blocks the NF-κB signalling pathway (84). SKI is a transcriptional repressor that interacts with SMAD and may be methylated by the PRMT5-methylosome protein 50 (MEP50)-SHANK-associated RH domain interactor (SHARPIN) complex, altering transcriptional regulation of the TGFβ signalling pathway (52). In HCC, PRMT9 activates the PI3K/Akt/GSK3β/Snail signalling pathway to regulate Snail, increasing cell migration and invasion through EMT (85). SHARPIN, an adaptor for the linear ubiquitin chain assembly complex, has an important role in the NF-κB signalling pathway. Activated PRMT5 controls the expression of SRY-box transcription factor 10 and melanocyte inducing transcription factor and inhibition of the transcriptional corepressor SKI by SHARPIN-dependent arginine demethylation, contributing to the occurrence of melanomagenesis (86). The expression of PRMT3 is upregulated in colorectal cancer and may stabilise the protein structure of c-MYC, and PRMT3 promotes the expression of c-MYC by interacting with c-MYC through the SAM-dependent MTase-PRMT domain (87). PRMT3 methylates hypoxia-inducible factor (HIF)1α at R282 and stabilizes the structure of HIF1α, while activating the HIF1/VEGFA signalling pathway to promote tumorigenesis (88). PRMT1, -5 and -7 regulate glioma-associated oncogene 1 (GLI1) and GLI2 activity (89). Methylation of GLI1 by PRMT1 upregulates its activity and promotes target gene expression. PRMT5 methylates GLI1 in the cytoplasm and increases GLI1 protein stability. Conversely, nuclear PRMT5 interacts with MENIN to inhibit the expression of growth arrest-specific protein 1, which facilitates Hedgehog ligand binding to Patched and indirectly downregulates GLI1 activity. PRMT7 methylates GLI2 to upregulate its activity through GLI2 dissociation and fusion inhibitors (89). PRMT1 expression is upregulated and promotes tumour cell growth in pancreatic ductal adenocarcinoma (PDAC). PRMT1 promotes β-catenin expression by binding -699 to -874 bp and -1,191 to -1,413 bp of the β-catenin promoter (90). Tumour suppressor protein von Hippel-Lindau interacts with PRMT3 and then forms a protein complex with Auxin response factor and regulates the methylation of p53 (91). PRMT3 protein expression is upregulated in patients with gemcitabine (GEM)-resistant pancreatic cancer. ATP binding cassette subfamily G member 2 (ABCG2) is a newly discovered target of PRMT3, and PRMT3 overexpression increases the methylation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) at R31, resulting in enhanced RNA-binding activity of hnRNPA1 and increased expression of ABCG2 mRNA. Therefore, PRMT3 methylates the RNA recognition motif of hnRNPA1 to promote the binding of hnRNPA1 and ABCG2 to enhance the resistance of pancreatic cancer to GEM (92). PRMT5 methylation of hnRNPA1 promotes the interaction of hnRNPA1 with internal ribosome entry site (IRES) RNA to promote IRES-dependent translation of cyclin D1 and c-MYC (93). The PRMT type 1 inhibitor MS023 is a potent inducer of colon cancer-cell differentiation with a wide therapeutic window. This finding may lead to the development of clinically effective anti-cancer drugs based on the mechanism of cancer cell differentiation (94).

 4. Participation in tumour immunity

PRMTs can modulate Toll-like receptor and interferon (IFN) activation at multiple levels to modulate immune responses (95). PRMT5 expression was observed to be negatively associated with antitumor immunity. After PRMT5 inhibition, the number of infiltrating immune cells increased and antitumour immunity was enhanced in immunocompetent mice (96). PRMT5 promotes antitumour immunity through two different intertumoral pathways. First, PRMT5-mediated interferon gamma inducible protein 16 (IFI16)/IFI204 methylation attenuates dsDNA-induced TANK binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) activation and chemokine production. dsDNA induced activation of TBK1-IRF3, as reflected by the levels of STING phosphorylation, dimerization and polymerization. PRMT5 methylation of IFI16/IFI204 impacts cyclic GMP-AMP synthase-stimulator of interferon genes (STING) signalling. Ectopically expressed IFI204 in B16 cells activated TBK1-IRF3 signalling and increased the expression of IFNB1 and C-C motif chemokine ligand 5 following dsDNA treatment. IFI204Mt1 (R12A) expression increased STING dimerization and polymerization following dsDNA stimuli, suggesting a critical role of IFI204 methylation on Arg12 in the dsDNA-stimulated STING pathway activation. PRMT5-mediated IFI16/IFI204 methylation attenuates dsDNA-induced TBK1-IRF3 activation and type I interferon and chemokine production. In addition, NLR family CARD domain containing 5, a master regulator of inflammasomes and antigen presentation pathways, was inversely correlated with PRMT5 expression. PRMT5 inhibits immune cell recruitment and activation as well as tumour recognition, thereby influencing tumour immune evasion. Likewise, inhibition of PRMT5 is expected to enhance the response of cold tumours to immune checkpoint therapy (96). MS023, a type I PRMT inhibitor, causes splicing of modulatory drugs, treatment alterations with intron retention and exon skipping, and these alterations result in substantial enrichment of major histocompatibility complex I-binding peptides. Of note, a fairly large proportion (up to 43%) of these putative neoantigens are immunogenic, resulting in neoantigen-specific CD8+ T-cell activation (97).

Controlling PRMT5 activity is a promising strategy for cancer therapy when host immunity against tumours occurs in a FOXP3-dependent manner (98). Arginine methylation occurs frequently at R27, R51 and R146 of FOXP3, but pharmacological inhibition of PRMT5 by DS-437 may reduce T-regulatory cell (Treg) functions and inhibits the methylation of FOXP3. Furthermore, DS-437 significantly enhanced the anti-tumour effects of anti-erbB2/neu monoclonal antibody targeted therapy in BALB/c mice, which bore CT26Her2 tumours, by inhibiting Treg function and induction of tumour immunity (98). Of note, FOXP3 also undergoes methylation on R48 and R51 by interacting with PRMT1. The inhibition of arginine methylation confers gene expression profiles representing type I helper T cells to FOXP3+ T cells, which resulted in attenuated suppressive activity (99). Otherwise, knockout of PRMT1 may enhance anti-programmed cell death receptor-1 immunotherapy in MC38-derived tumours in isogenic C57BL/6 mice (100). Of note, the PRMT1 polymorphism rs975484 modulates programmed cell death ligand-1 (PD-L1) and PD-L2 levels and serves as a predictor of immune checkpoint blockade efficiency in HCC (101). CARM1 was identified as a negative regulator of tumour-specific T cells in B16F10 melanoma-resistant C57BL/6 mice (102).

Furthermore, studies have indicated that type I PRMT inhibitors may enhance the effect of immunotherapy. PT1001B enhances antitumor immunity, and combining it with anti-PD-L1 checkpoint inhibitors provides a potential strategy to overcome anti-PD-L1 resistance in PDAC (103). MS023 treatment significantly improved anti-PD1 therapy in C57BL/6 tumour-bearing mice (104). Therefore, further studies are needed to determine the effect of PRMT inhibition, not only on tumour cells, but also on other cell types in the tumour microenvironment, including immune cells and stromal cells.

 5. Participation in metabolic reprogramming

Metabolic reprogramming is an important process by which cancer cells adapt to high energy demands and supplement biosynthetic needs, and numerous cancers switch their tumour cell metabolism to the glycolytic pathway under oxygen-rich conditions. Therefore, inhibition of metabolic reprogramming by modulating different metabolic pathways in tumours provides a new strategy for cancer therapy (105,106).

In pancreatic cancer, PRMT3 may methylate GAPDH at R248 to enhance cancer glycolysis and mitochondrial respiration. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. Both intermediates in the glycolytic pathway and the tricarboxylic acid cycle are enriched in PRMT3-expressed cells. In addition, these cells exhibit an increased extracellular acidification rate and oxygen consumption rate. Double blockade of GAPDH and mitochondrial respiration will be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer (107). Esophageal squamous cell carcinoma (ESCC) is associated with elevated asymmetric and systemic arginine dimethylarginine. PRMT1, PRMT5, ornithine decarboxylase 1 and nitric oxide (NO) synthase 2 are overexpressed, and arginase 1, arginase 2 and dimethylarginine dimethylaminohydrolase 1 are downregulated in tumours compared to adjacent tissues. Arginine bioavailability increased and citrulline decreased along with ESCC advancement. In short, metabolic reprogramming in ESCC manifests as alterations in the L-arginine/NO pathway (108). In HCC, PRMT3 mediates ADMA modification of lactate dehydrogenase A (LDHA) at R112. LDHA-R112K-mutant-expressing cells exhibited a decrease in LDH activity, HCC cell glycolysis and proliferation (109). In chronic myeloid leukemia (CML), loss of PRMT7 resulted in reduced expression of glycine decarboxylase, leading to the reprograming of glycine metabolism to generate methylglyoxal, which is detrimental to leukemia stem cells (LSCs). These findings link histone arginine methylation with glycine metabolism, while suggesting PRMT7 as a potential therapeutic target for the eradication of LSCs in CML (109).

 6. Methylation profiles of PRMTs

Despite the relevance of PRMTs for signal transduction, metabolism, transcription and other cellular phenotypes, the methylation profiles of protein arginine remain understudied. The function of PRMTs under physiological and pathological conditions often depends on methyltransferase activity. Therefore, comprehensively revealing the substrates of PRMTs is the key to exploring their functions and underlying molecular mechanisms.

Combining two newly developed methylation sequencing methods, immunoaffinity purification and high pH strong cation exchange, may improve the coverage of protein methylation and reveal new PRMT1 targets (110). After knockout of PRMT1, 127 arginine methylation sites on 78 proteins were significantly changed. In contrast, only one lysine methylation site was significantly changed after PRMT1 knockdown, indicating that amino acid methylation was not affected by PRMT1 knockdown. In PRMT1-knockout cells, 114 MMA sites were found to be significantly altered on proteins enriched in the mRNA metabolic process. A high-confidence list of 18 PRMT1 substrates and 12 methylation sites scavenged by other PRMTs in the absence of PRMT1 activity was found through integrative analysis of MMA and DMA. Most importantly, the methylation site hnRNPA1 R206 switched from ADMA to SDMA after PRMT1 knockout (110).

High-resolution mass spectrometry combined with SILAC technology was used to analyse the arginine methylation regulated by PRMT7 in 293 cells (111). A total of 1,031 MMA sites of 513 proteins were detected and a two-fold decrease in monomethylation levels at 297 arginine sites in 174 proteins was found, termed the PRMT7 methylome. During this process, the methylation of 176 MMA sites in 108 proteins disappeared completely. After treatment with the PRMT7-specific inhibitor SGC3027, 503 MMA sites of 274 proteins were more than two-fold reduced, and ~60% of PRMT7-regulated substrates were also inhibited. The same method was also used to identify the methylated substrates of PRMT4 and -5, representing type I and II PRMTs, respectively. The PRMT4 methyl group (two-fold decrease) includes 301 proteins with 660 methylation sites, while the PRMT5 methyl group (two-fold decrease) includes 244 proteins with 429 methylation sites. PRMT4 substrates, such as mediator complex subunit 12, SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1 and E1A binding protein p300, and PRMT5 substrates, such as FUS RNA binding protein, hnRNPA1 and survival of motor neuron 1, have also been identified. Most importantly, PRMT4, -5 and -7 coregulate alternative splicing in an enzyme-dependent manner and share a number of RNA splicing factors, such as hnRNPA1; furthermore, hnRNPA1 arginine methylation is required for the growth of various cancer cells (116). Taken together, the methylation profiles of PRMTs indicated that hnRNAPA1 has a role of co-RNA splicing factor in various arginine methylation modification processes and may also promote the transformation of ADMA to SDMA. Further study of its mechanism will reveal the types of arginine methylation.

 7. Future outlook

While much important progress has been made in research on PRMT function, the complexity and significance of gene post-transcriptional processing determine the diversity of the PRMT regulatory mechanisms. The regulatory effect of PRMTs on the function of RBP clearly exemplifies the important regulatory role of arginine methylation in post-transcriptional processing. Although numerous important advances have been made in the study of PRMTs regulating the function of RBP, various questions remain to be answered in the field of cancer, such as how a single arginine methylation site determines the function of specific proteins, how different PRMT family members synergistically regulate the occurrence of specific substrate methylation and how arginine methylation modifications are recognized and removed. In addition, the sequence characteristic of the target RNA directly affected by RBP and how arginine methylation regulates the interaction between RBP and its target RNA at the genome-wide level are also key questions to be solved. In addition, PRMTs directly methylate numerous proteins to control their subcellular localization, protein-protein interactions, stability or activity. Many of these contribute to oncogenic transformation, and thus, evaluation of potential PRMT inhibitors is warranted. What remains to be established is how the inhibition of arginine methylation may be integrated with immunotherapeutic approaches to achieve a maximal, long-lasting therapeutic effect.

 Availability of data and materials

Not applicable.

 Authors' contributions

KW, CN and HL were involved in the conception of the review. KW wrote the manuscript and performed the literature search. KW and LF reviewed and edited the final manuscript. All authors have read and approved the final manuscript. Data authentication is not applicable.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

 Acknowledgments

Not applicable.

 References VuLDGevaertKDe SmetIProtein language: Post-translational modifications talking to each otherTrends Plant Sci2310681080201810.1016/j.tplants.2018.09.00430279071 JarroldJDaviesCCPRMTs and arginine methylation: Cancer's best-kept secret?Trends Mol Med259931009201910.1016/j.molmed.2019.05.00731230909 PaikWKKimSEnzymatic methylation of protein fractions from calf thymus nucleiBiochem Biophys Res Commun291420196710.1016/0006-291X(67)90533-56055181 LinWJGaryJDYangMCClarkeSHerschmanHRThe mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferaseJ Biol Chem2711503415044199610.1074/jbc.271.25.150348663146 BlancRSRichardSArginine methylation: The coming of ageMol Cell65824201710.1016/j.molcel.2016.11.00328061334 BedfordMTClarkeSGProtein arginine methylation in mammals: Who, what, and whyMol Cell33113200910.1016/j.molcel.2008.12.013191504233372459 HughesRMWatersMLArginine methylation in a beta-hairpin peptide: Implications for Arg-pi interactions, DeltaCp(o), and the cold denatured stateJ Am Chem Soc1281273512742200610.1021/ja061656g17002367 ObianyoOCauseyCPJonesJEThompsonPRActivity-based protein profiling of protein arginine methyltransferase 1ACS Chem Biol611271135201110.1021/cb2001473218382533199286 GuiSWooderchakWLDalyMPPorterPJJohnsonSJHevelJMInvestigation of the molecular origins of protein-arginine methyltransferase I (PRMT1) product specificity reveals a role for two conserved methionine residuesJ Biol Chem2862911829126201110.1074/jbc.M111.224097216970823190719 GuiSGathiakaSLiJQuJAcevedoOHevelJMA remodeled protein arginine methyltransferase 1 (PRMT1) generates symmetric dimethylarginineJ Biol Chem28993209327201410.1074/jbc.M113.535278244783143979365 YoshimotoTBoehmMOliveMCrookMFSanHLangenickelTNabelEGThe arginine methyltransferase PRMT2 binds RB and regulates E2F functionExp Cell Res31220402053200610.1016/j.yexcr.2006.03.00116616919 FrankelAClarkeSPRMT3 is a distinct member of the protein arginine N-methyltransferase family. Conferral of substrate specificity by a zinc-finger domainJ Biol Chem2753297432982200010.1074/jbc.M00644520010931850 ShishkovaEZengHLiuFKwiecienNWHebertASCoonJJXuWGlobal mapping of CARM1 substrates defines enzyme specificity and substrate recognitionNat Commun815571201710.1038/ncomms15571285372685458078 SunLWangMLvZYangNLiuYBaoSGongWXuRMStructural insights into protein arginine symmetric dimethylation by PRMT5Proc Natl Acad Sci USA1082053820543201110.1073/pnas.1106946108221437703251124 OkunoKAkiyamaYShimadaSNakagawaMTaniokaTInokuchiMYamaokaSKojimaKTanakaSAsymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progressionCarcinogenesis401526201910.1093/carcin/bgy147 HasegawaMToma-FukaiSKimJDFukamizuAShimizuTProtein arginine methyltransferase 7 has a novel homodimer-like structure formed by tandem repeatsFEBS Lett58819421948201410.1016/j.febslet.2014.03.05324726727 LeeJSayeghJDanielJClarkeSBedfordMTPRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase familyJ Biol Chem2803289032896200510.1074/jbc.M50694420016051612 HadjikyriacouAYangYEspejoABedfordMTClarkeSGUnique features of human protein arginine methyltransferase 9 (PRMT9) and its substrate RNA splicing factor SF3B2J Biol Chem2901672316743201510.1074/jbc.M115.659433259793444505422 FultonMDCaoMHoMCZhaoXZhengYGThe macromolecular complexes of histones affect protein arginine methyltransferase activitiesJ Biol Chem297101123202110.1016/j.jbc.2021.101123344922708511957 OsborneTCObianyoOZhangXChengXThompsonPRProtein arginine methyltransferase 1: Positively charged residues in substrate peptides distal to the site of methylation are important for substrate binding and catalysisBiochemistry461337013381200710.1021/bi701558t179609152723811 WaldmannTIzzoAKamieniarzKRichterFVoglerCSargBLindnerHYoungNLMittlerGGarciaBASchneiderRMethylation of H2AR29 is a novel repressive PRMT6 targetEpigenetics Chromatin411201110.1186/1756-8935-4-11217747913164600 BranscombeTLFrankelALeeJHCookJRYangZPestkaSClarkeSPRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteinsJ Biol Chem2763297132976200110.1074/jbc.M10541220011413150 KarkhanisVWangLTaeSHuYJImbalzanoANSifSProtein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POLD1J Biol Chem2872980129814201210.1074/jbc.M112.378281227614213436169 HuGYanCXiePCaoYShaoJGeJPRMT2 accelerates tumorigenesis of hepatocellular carcinoma by activating Bcl2 via histone H3R8 methylationExp Cell Res394112152202010.1016/j.yexcr.2020.11215232574605 DongFLiQYangCHuoDWangXAiCKongYSunXWangWZhouYPRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastomaNat Commun94552201810.1038/s41467-018-06968-7303820836208368 YangYLuYEspejoAWuJXuWLiangSBedfordMTTDRD3 is an effector molecule for arginine-methylated histone marksMol Cell4010161023201010.1016/j.molcel.2010.11.024211726653090733 XuJRichardSCellular pathways influenced by protein arginine methylation: Implications for cancerMol Cell8143574368202110.1016/j.molcel.2021.09.011346190918571027 FuTLvXKongQYuanCA novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasionOncotarget85480954820201710.18632/oncotarget.18957289033845589623 ChiangKZielinskaAEShaabanAMSanchez-BailonMPJarroldJClarkeTLZhangJFrancisAJonesLJSmithSPRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expressionCell Rep2134983513201710.1016/j.celrep.2017.11.096292623295746596 CaoLWuGZhuJTanZShiDWuXTangMLiZHuYZhangSGenotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasisNat Commun103761201910.1038/s41467-019-11696-7 MiglioriVMüllerJPhalkeSLowDBezziMMokWCSahuSKGunaratneJCapassoPBassiCSymmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenanceNat Struct Mol Biol19136144201210.1038/nsmb.220922231400 MitchellLHDrewAERibichSARiouxNSwingerKKJacquesSLLingarajTBoriack-SjodinPAWatersNJWigleTJAryl pyrazoles as potent inhibitors of arginine methyltransferases: Identification of the first PRMT6 tool compoundACS Med Chem Lett6655659201510.1021/acsmedchemlett.5b00071261015694468411 ZhangBDongSZhuRHuCHouJLiYZhaoQShaoXBuQLiHTargeting protein arginine methyltransferase 5 inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3Oncotarget62279922811201510.18632/oncotarget.4332260783544673200 DengXShaoGZhangHTLiCZhangDChengLElzeyBDPiliRRatliffTLHuangJHuCDProtein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growthOncogene3612231231201710.1038/onc.2016.2875322258 YaoBGuiTZengXDengYWangZWangYYangDLiQXuPHuRPRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signalingGenome Med1358202110.1186/s13073-021-00871-5338536628048298 KaushikSLiuFVeazeyKJGaoGDasPNevesLFLinKZhongYLuYGiulianiVGenetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AMLLeukemia32499509201810.1038/leu.2017.206 YangLMaDWCaoYPLiDZZhouXFengJFBaoJPRMT5 functionally associates with EZH2 to promote colorectal cancer progression through epigenetically repressing CDKN2B expressionTheranostics1137423759202110.7150/thno.53023336648597914347 GurungBFengZHuaXMenin directly represses Gli1 expression independent of canonical Hedgehog signalingMol Cancer Res1112151222201310.1158/1541-7786.MCR-13-0170239280574028077 GurungBFengZIwamotoDVThielAJinGFanCMNgJMCurranTHuaXMenin epigenetically represses Hedgehog signaling in MEN1 tumor syndromeCancer Res7326502658201310.1158/0008-5472.CAN-12-3158235805764100916 KrebsAMMitschkeJLasierra LosadaMSchmalhoferOBoerriesMBuschHBoettcherMMougiakakosDReichardtWBronsertPThe EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancerNat Cell Biol19518529201710.1038/ncb351328414315 GaoYZhaoYZhangJLuYLiuXGengPHuangBZhangYLuJThe dual function of PRMT1 in modulating epithelial-mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1Sci Rep619874201610.1038/srep19874268134954728496 ChenHLortonBGuptaVShechterDA TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repressionOncogene36373386201710.1038/onc.2016.205 LiuRGaoJYangYQiuRZhengYHuangWZengYHouYWangSLengSPHD finger protein 1 (PHF1) is a novel reader for histone H4R3 symmetric dimethylation and coordinates with PRMT5-WDR77/CRL4B complex to promote tumorigenesisNucleic Acids Res4666086626201810.1093/nar/gky461298466706061854 SiarheyevaASenisterraGAllali-HassaniADongADobrovetskyEWasneyGAChauIMarcellusRHajianTLiuFAn allosteric inhibitor of protein arginine methyltransferase 3Structure2014251435201210.1016/j.str.2012.06.00122795084 JainKClarkeSGPRMT7 as a unique member of the protein arginine methyltransferase family: A reviewArch Biochem Biophys6653645201910.1016/j.abb.2019.02.014308024336461449 PalSVishwanathSNErdjument-BromageHTempstPSifSHuman SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genesMol Cell Biol2496309645200410.1128/MCB.24.21.9630-9645.200415485929522266 ScaglioneAPatzigJLiangJFrawleyRBokJMelaAYattahCZhangJTeoSXZhouTPRMT5-mediated regulation of developmental myelinationNat Commun92840201810.1038/s41467-018-04863-9300265606053423 JingPZhaoNYeMZhangYZhangZSunJWangZZhangJGuZProtein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signalingCancer Lett4273848201810.1016/j.canlet.2018.04.01929679612 KarkhanisVAlinariLOzerHGChungJZhangXSifSBaiocchiRAProtein arginine methyltransferase 5 represses tumor suppressor miRNAs that down-regulate CYCLIN D1 and c-MYC expression in aggressive B-cell lymphomaJ Biol Chem29511651180202010.1016/S0021-9258(17)49877-26996892 ChoECZhengSMunroSLiuGCarrSMMoehlenbrinkJLuYCStimsonLKhanOKonietznyRArginine methylation controls growth regulation by E2F-1EMBO J3117851797201210.1038/emboj.2012.17223272183321197 LiuLZhaoXZhaoLLiJYangHZhuZLiuJHuangGArginine methylation of SREBP1a via PRMT5 promotes de novo lipogenesis and tumor growthCancer Res7612601272201610.1158/0008-5472.CAN-15-176626759235 LuXFernandoTMLossosCYusufovaNLiuFFontáLDurantMGengHMelnickJLuoYPRMT5 interacts with the BCL6 oncoprotein and is required for germinal center formation and lymphoma cell survivalBlood13220262039201810.1182/blood-2018-02-831438300824946236466 YuJShinBParkESYangSChoiSKangMRhoJProtein arginine methyltransferase 1 regulates herpes simplex virus replication through ICP27 RGG-box methylationBiochem Biophys Res Commun391322328201010.1016/j.bbrc.2009.11.057 FronzKGüttingerSBurkertKKühnUStöhrNSchierhornAWahleEArginine methylation of the nuclear poly(a) binding protein weakens the interaction with its nuclear import receptor, transportinJ Biol Chem2863298632994201110.1074/jbc.M111.273912218080653190935 KatsunoYQinJOses-PrietoJWangHJackson-WeaverOZhangTLamouilleSWuJBurlingameAXuJDerynckRArginine methylation of SMAD7 by PRMT1 in TGF-β-induced epithelial-mesenchymal transition and epithelial stem-cell generationJ Biol Chem2931305913072201810.1074/jbc.RA118.002027299075696109915 ClarkeTLSanchez-BailonMPChiangKReynoldsJJHerrero-RuizJBandeirasTMMatiasPMMaslenSLSkehelJMStewartGSDaviesCCPRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombinationMol Cell65900916.e7201710.1016/j.molcel.2017.01.019282386545344794 HamardPJSantiagoGELiuFKarlDLMartinezCManNMookhtiarAKDuffortSGreenblattSVerdunRENimerSDPRMT5 regulates DNA repair by controlling the alternative splicing of histone-modifying enzymesCell Rep2426432657201810.1016/j.celrep.2018.08.002301844996322662 HellmuthSGutiérrez-CaballeroCLlanoEPendásAMStemmannOLocal activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformationEMBO J37e99184201810.15252/embj.201899184303053036236338 VadnaisCChenRFraszczakJYuZBoulaisJPinderJFrankDKhandanpourCHébertJDellaireGGFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1Nat Commun91418201810.1038/s41467-018-03817-5296510205897347 KarakashevSFukumotoTZhaoBLinJWuSFatkhutdinovNParkPHSemenovaGJeanSCadungogMGEZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibitionCancer Cell37157167.e6202010.1016/j.ccell.2019.12.015320044427155421 WeiXYangJAdairSJOzturkHKuscuCLeeKYKaneWJO'HaraPELiuDDemirlenkYMTargeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cellsProc Natl Acad Sci USA1172806828079202010.1073/pnas.2009899117330976617668168 LiYChitnisNNakagawaHKitaYNatsugoeSYangYLiZWasikMKlein-SzantoAJRustgiAKDiehlJAPRMT5 is required for lymphomagenesis triggered by multiple oncogenic driversCancer Discov5288303201510.1158/2159-8290.CD-14-0625255826974355177 JanssonMDurantSTChoECSheahanSEdelmannMKesslerBLa ThangueNBArginine methylation regulates the p53 responseNat Cell Biol1014311439200810.1038/ncb180219011621 RochaCRRSilvaMMQuinetACabral-NetoJBMenckCFMDNA repair pathways and cisplatin resistance: An intimate relationshipClinics (Sao Paulo)73Suppl 1e478s201810.6061/clinics/2018/e478s302081656113849 McCabeNTurnerNCLordCJKluzekKBialkowskaASwiftSGiavaraSO'ConnorMJTuttANZdzienickaMZDeficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibitionCancer Res6681098115200610.1158/0008-5472.CAN-06-014016912188 PeshkinBNAlabekMLIsaacsCBRCA1/2 mutations and triple negative breast cancersBreast Dis322533201010.3233/BD-2010-0306 HuangTYangYSongXWanXWuBSastryNHorbinskiCMZengCTiekDGoenkaAPRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cellsMol Cell8112761291.e9202110.1016/j.molcel.2021.01.015335397877979509 Sanchez-BailonMPChoiSYDufficyERSharmaKMcNeeGSGunnellEChiangKSahayDMaslenSStewartGSArginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repairNat Commun126313202110.1038/s41467-021-26413-6347286208564520 DvingeHKimEAbdel-WahabOBradleyRKRNA splicing factors as oncoproteins and tumour suppressorsNat Rev Cancer16413430201610.1038/nrc.2016.51272822505094465 BonnalSCLópez-OrejaIValcárcelJRoles and mechanisms of alternative splicing in cancer-implications for careNat Rev Clin Oncol17457474202010.1038/s41571-020-0350-x32303702 FongJYPignataLGoyPAKawabataKCLeeSCKohCMMusianiDMassignaniEKotiniAGPensonATherapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylationCancer Cell36194209.e9201910.1016/j.ccell.2019.07.003314086197194031 GuccioneERichardSThe regulation, functions and clinical relevance of arginine methylationNat Rev Mol Cell Biol20642657201910.1038/s41580-019-0155-x31350521 RadzisheuskayaAShliahaPVGrinevVLorenziniEKovalchukSShlyuevaDGorshkovVHendricksonRCJensenONHelinKPRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemiaNat Struct Mol Biol269991012201910.1038/s41594-019-0313-z316116886858565 MusianiDBokJMassignaniEWuLTabaglioTIppolitoMRCuomoAOzbekUZorgatiHGhoshdastiderUProteomics profiling of arginine methylation defines PRMT5 substrate specificitySci Signal12eaat8388201910.1126/scisignal.aat838830940768 CaiTCinkornpuminJKYuZVillarrealODPastorWARichardSDeletion of RBMX RGG/RG motif in Shashi-XLID syndrome leads to aberrant p53 activation and neuronal differentiation defectsCell Rep36109337202110.1016/j.celrep.2021.10933734260915 GerhartSVKellnerWAThompsonCPappalardiMBZhangXPMontes de OcaRPenebreEDuncanKBoriack-SjodinALeBActivation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicingSci Rep89711201810.1038/s41598-018-28002-y299461506018746 AbuHammadSCullinaneCMartinCBacolasZWardTChenHSlaterAArdleyKKirbyLChanKTRegulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanomaProc Natl Acad Sci USA1161799018000201910.1073/pnas.1901323116314398206731642 RoworthAPCarrSMLiuGBarczakWMillerRLMunroSKanapinASamsonovaALa ThangueNBArginine methylation expands the regulatory mechanisms and extends the genomic landscape under E2F controlSci Adv5eaaw4640201910.1126/sciadv.aaw4640312498706594773 YangYHadjikyriacouAXiaZGayatriSKimDZurita-LopezCKellyRGuoALiWClarkeSGBedfordMTPRMT9 is a type II methyltransferase that methylates the splicing factor SAP145Nat Commun66428201510.1038/ncomms7428257370134351962 SureshSHuardSBrissonANématiFDakroubRPoulardCYeMMartelEReyesCSilvestreDCPRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancerCancers (Basel)14306202210.3390/cancers14020306350534708774276 FedoriwARajapurkarSRO'BrienSGerhartSVMitchellLHAdamsNDRiouxNLingarajTRibichSAPappalardiMBAnti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP lossCancer Cell36100114.e25201910.1016/j.ccell.2019.05.01431257072 WeiHWangBMiyagiMSheYGopalanBHuangDBGhoshGStarkGRLuTPRMT5 dimethylates R30 of the p65 subunit to activate NF-κBProc Natl Acad Sci USA1101351613521201310.1073/pnas.1311784110 TanakaHHoshikawaYOh-haraTKoikeSNaitoMNodaTAraiHTsuruoTFujitaNPRMT5, a novel TRAIL receptor-binding protein, inhibits TRAIL-induced apoptosis via nuclear factor-kappaB activationMol Cancer Res7557569200910.1158/1541-7786.MCR-08-019719372584 GullàAHideshimaTBianchiGFulcinitiMKemal SamurMQiJTaiYTHaradaTMorelliEAmodioNProtein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myelomaLeukemia329961002201810.1038/leu.2017.334 JiangHZhouZJinSXuKZhangHXuJSunQWangJXuJPRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3β/Snail signalingCancer Sci10914141427201810.1111/cas.13598296038305980302 TamiyaHKimHKlymenkoOKimHFengYZhangTHanJYMuraoASnipasSJJilaveanuLSHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growthJ Clin Invest128517530201810.1172/JCI954105749505 HuYSuYHeYLiuWXiaoBArginine methyltransferase PRMT3 promote tumorigenesis through regulating c-MYC stabilization in colorectal cancerGene791145718202110.1016/j.gene.2021.14571833991650 ZhangXWangKFengXWangJChuYJiaCHeQChenCPRMT3 promotes tumorigenesis by methylating and stabilizing HIF1α in colorectal cancerCell Death Dis121066202110.1038/s41419-021-04352-w AbeYTanakaNFine-tuning of GLI activity through arginine methylation: its mechanisms and functionCells91973202010.3390/cells9091973328590417565022 SongCChenTHeLMaNLiJARongYFFangYLiuMXieDLouWPRMT1 promotes pancreatic cancer growth and predicts poor prognosis. Cell Oncol (Dordr)4351622020 LaiYSongMHakalaKWeintraubSTShiioYProteomic dissection of the von Hippel-Lindau (VHL) interactomeJ Proteome Res1051755182201110.1021/pr200642c219427153208728 HsuMCPanMRChuPYTsaiYLTsaiCHShanYSChenLTHungWCProtein arginine methyltransferase 3 enhances chemoresistance in pancreatic cancer by methylating hnRNPA1 to increase ABCG2 expressionCancers (Basel)118201810.3390/cancers11010008305775706356582 GaoGDharSBedfordMTPRMT5 regulates IRES-dependent translation via methylation of hnRNP A1Nucleic Acids Res45435943692017281156265416833 PlotnikovAKozerNCohenGCarvalhoSDubersteinSAlmogOSolmeskyLJShurrushKABabaevIBenjaminSPRMT1 inhibition induces differentiation of colon cancer cellsSci Rep1020030202010.1038/s41598-020-77028-8332087617676271 SenguptaSKennemerAPatrickKTsichlisPGuerau-de-ArellanoMProtein arginine methyltransferase 5 in T lymphocyte biologyTrends Immunol41918931202010.1016/j.it.2020.08.007328888199425078 KimHKimHFengYLiYTamiyaHTocciSRonaiZAPRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunitySci Transl Med12eaaz5683202010.1126/scitranslmed.aaz5683326414917508354 ElliottKNilssonJVan den EyndenJPharmacologic RNA splicing modulation: A novel mechanism to enhance neoantigen-directed anti-tumor immunity and immunotherapy responseSignal Transduct Target Ther6373202110.1038/s41392-021-00789-9347118028553762 NagaiYJiMQZhuFXiaoYTanakaYKambayashiTFujimotoSGoldbergMMZhangHLiBPRMT5 associates with the FOXP3 homomer and when disabled enhances targeted p185erbB2/neu tumor immunotherapyFront Immunol10174201910.3389/fimmu.2019.00174 KagoyaYSaijoHMatsunagaYGuoTSasoKAnczurowskiMWangCHSugataKMurataKButlerMOArginine methylation of FOXP3 is crucial for the suppressive function of regulatory T cellsJ Autoimmun971021201910.1016/j.jaut.2018.09.011 HouJWangYShiLChenYXuCSaeediAPanKBohatREganNAMcKenzieJAIntegrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulatorsJ Immunother Cancer9e001819202110.1136/jitc-2020-001819335895277887353 SchonfeldMZhaoJKomatzAWeinmanSATikhanovichIThe polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinomaJ Biol Chem29571267137202010.1074/jbc.RA120.013401322458897242710 KumarSZengZBagatiATayRESanzLAHartonoSRItoYAbderazzaqFHatchiEJiangPCARM1 inhibition enables immunotherapy of resistant tumors by dual action on tumor cells and T cellsCancer Discov1120502071202110.1158/2159-8290.CD-20-1144337072348338742 ZhengNNZhouMSunFHuaiMXZhangYQuCYShenFXuLMCombining protein arginine methyltransferase inhibitor and anti-programmed death-ligand-1 inhibits pancreatic cancer progressionWorld J Gastroenterol2637373749202010.3748/wjg.v26.i26.3737327740547383845 LuSXDe NeefEThomasJDSabioERousseauBGigouxMKnorrDAGreenbaumBElhanatiYHoggSJPharmacologic modulation of RNA splicing enhances anti-tumor immunityCell18440324047.e31202110.1016/j.cell.2021.05.038341713098684350 TennantDADuránRVGottliebETargeting metabolic transformation for cancer therapyNat Rev Cancer10267277201010.1038/nrc281720300106 Ganapathy-KanniappanSGeschwindJFTumor glycolysis as a target for cancer therapy: Progress and prospectsMol Cancer12152201310.1186/1476-4598-12-152242989084223729 HsuMCTsaiYLLinCHPanMRShanYSChengTYChengSHChenLTHungWCProtein arginine methyltransferase 3-induced metabolic reprogramming is a vulnerable target of pancreatic cancerJ Hematol Oncol1279201910.1186/s13045-019-0769-7313242086642535 Bednarz-MisaIFortunaPFleszarMGLewandowskiŁDiakowskaDRosińczukJKrzystek-KorpackaMEsophageal squamous cell carcinoma is accompanied by local and systemic changes in L-arginine/NO pathwayInt J Mol Sci216282202010.3390/ijms21176282328726697503331 LeiYHanPChenYWangHWangSWangMLiuJYanWTianDLiuMProtein arginine methyltransferase 3 promotes glycolysis and hepatocellular carcinoma growth by enhancing arginine methylation of lactate dehydrogenase AClin Transl Med12e686202210.1002/ctm2.686350900768797063 HartelNGChewBQinJXuJGrahamNADeep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targetsMol Cell Proteomics1821492164201910.1074/mcp.RA119.001625314515476823857 LiWJHeYHYangJJHuGSLinYARanTPengBLXieBLHuangMFGaoXProfiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growthNat Commun121946202110.1038/s41467-021-21963-1337824018007824 IbergANEspejoAChengDKimDMichaud-LevesqueJRichardSBedfordMTArginine methylation of the histone H3 tail impedes effector bindingJ Biol Chem28330063010200810.1074/jbc.C700192200 NeaultMMalletteFAVogelGMichaud-LevesqueJRichardSAblation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressorNucleic Acids Res4095139521201210.1093/nar/gks764229040643479207 LortonBMHarijanRKBurgosESBonannoJBAlmoSCShechterDA binary arginine methylation switch on histone H3 arginine 2 regulates its interaction with WDR5Biochemistry5936963708202010.1021/acs.biochem.0c00035322079707529705 GuccioneEBassiCCasadioFMartinatoFCesaroniMSchuchlautzHLüscherBAmatiBMethylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusiveNature449933937200710.1038/nature0616617898714 DacwagCSOhkawaYPalSSifSImbalzanoANThe protein arginine methyltransferase Prmt5 is required for myogenesis because it facilitates ATP-dependent chromatin remodelingMol Cell Biol27384394200710.1128/MCB.01528-061800640 TarighatSSSanthanamRFrankhouserDRadomskaHSLaiHAnghelinaMWangHHuangXAlinariLWalkerAThe dual epigenetic role of PRMT5 in acute myeloid leukemia: Gene activation and repression via histone arginine methylationLeukemia30789799201610.1038/leu.2015.308 ZhangZNikolaiBCGatesLAJungSYSiwakEBHeBRiceAPO'MalleyBWFengQCrosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latencyNucleic Acids Res4593489360201710.1093/nar/gkx550286371815766202 CheungNFungTKZeisigBBHolmesKRaneJKMowenKAFinnMGLenhardBChanLCSoCWTargeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemiaCancer Cell293248201610.1016/j.ccell.2015.12.007267665894712026 MinZXiaomengLZhengLYanggeDXuejiaoLLongweiLXiaoZYunsongLPingZYongshengZAsymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648Cell Death Dis10581201910.1038/s41419-019-1815-7313787836680051 ZhangYvan HarenMJMartinNIPeptidic transition state analogues as PRMT inhibitorsMethods1752429202010.1016/j.ymeth.2019.08.003 HameyJJRakowSBouchardCSenstJMKolbPBauerUMWilkinsMRHart-SmithGSystematic investigation of PRMT6 substrate recognition reveals broad specificity with a preference for an RG motif or basic and bulky residuesFEBS J28856685691202110.1111/febs.1583733764612 ZhaoQRankGTanYTLiHMoritzRLSimpsonRJCerrutiLCurtisDJPatelDJAllisCDPRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencingNat Struct Mol Biol16304311200910.1038/nsmb.1568192344655120857 JainKJinCYClarkeSGEpigenetic control via allosteric regulation of mammalian protein arginine methyltransferasesProc Natl Acad Sci USA1141010110106201710.1073/pnas.1706978114288745635617285 Di LorenzoABedfordMTHistone arginine methylationFEBS Lett58520242031201110.1016/j.febslet.2010.11.010 AvasaralaSVan ScoykMKaruppusamy RathinamMKZerayesusSZhaoXZhangWPergandeMRBorgiaJADeGregoriJPortJDPRMT1 is a novel regulator of epithelial-mesenchymal-transition in non-small cell lung cancerJ Biol Chem2901347913489201510.1074/jbc.M114.636050258472394505594 ZhaoZRahmanMAChenZGShinDMMultiple biological functions of Twist1 in various cancersOncotarget82038020393201710.18632/oncotarget.14608280999105386770 JobertLArgentiniMToraLPRMT1 mediated methylation of TAF15 is required for its positive gene regulatory functionExp Cell Res31512731286200910.1016/j.yexcr.2008.12.00819124016 MizutaniSYoshidaTZhaoXNimerSDTaniwakiMOkudaTLoss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasisBr J Haematol170859873201510.1111/bjh.13499260103964996932 YamagataKDaitokuHTakahashiYNamikiKHisatakeKKakoKMukaiHKasuyaYFukamizuAArginine methylation of FOXO transcription factors inhibits their phosphorylation by AktMol Cell32221231200810.1016/j.molcel.2008.09.01318951090 LiuLMSunWZFanXZXuYLChengMBZhangYMethylation of C/EBPα by PRMT1 inhibits its tumor-suppressive function in breast cancerCancer Res7928652877201910.1158/0008-5472.CAN-18-321131015230 FronzKOttoSKölbelKKühnUFriedrichHSchierhornABeck-SickingerAGOstareck-LedererAWahleEPromiscuous modification of the nuclear poly(A)-binding protein by multiple protein-arginine methyltransferases does not affect the aggregation behaviorJ Biol Chem2832040820420200810.1074/jbc.M80232920018495660 BoisvertFMRhieARichardSDohertyAJThe GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activityCell Cycle418341841200510.4161/cc.4.12.225016294045 BoisvertFMDéryUMassonJYRichardSArginine methylation of MRE11 by PRMT1 is required for DNA damage checkpoint controlGenes Dev19671676200510.1101/gad.1279805157413141065720 GuendelICarpioLPedatiCSchwartzATealCKashanchiFKehn-HallKMethylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor functionPLoS One5e11379201010.1371/journal.pone.0011379206140092894074 HuangLWangZNarayananNYangYArginine methylation of the C-terminus RGG motif promotes TOP3B topoisomerase activity and stress granule localizationNucleic Acids Res4630613074201810.1093/nar/gky103294714955888246 FriesenWJPaushkinSWyceAMassenetSPesiridisGSVan DuyneGRappsilberJMannMDreyfussGThe methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteinsMol Cell Biol2182898300200110.1128/MCB.21.24.8289-8300.20011171326699994 ZhangLTranNTSuHWangRLuYTangHAoyagiSGuoAKhodadadi-JamayranAZhouDCross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicingElife4e07938201510.7554/eLife.07938265752924775220 LiZWangDLuJHuangBWangYDongMFanDLiHGaoYHouPMethylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasisCell Death Differ2732263242202010.1038/s41418-020-00615-9328954887853151 Le RomancerMTreilleuxILeconteNRobin-LespinasseYSentisSBouchekioua-BouzaghouKGoddardSGobert-GosseSCorboLRegulation of estrogen rapid signaling through arginine methylation by PRMT1Mol Cell31212221200810.1016/j.molcel.2008.05.02518657504 NakaiKXiaWLiaoHWSaitoMHungMCYamaguchiHThe role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cellsBreast Cancer257480201810.1007/s12282-017-0790-z ChoucairAPhamTHOmarjeeSJacquemettonJKassemLTrédanORambaudJMarangoniECorboLTreilleuxILe RomancerMThe arginine methyltransferase PRMT1 regulates IGF-1 signaling in breast cancerOncogene3840154027201910.1038/s41388-019-0694-9306926336755991 WangLJiaZXieDZhaoTTanZZhangSKongFWeiDXieKMethylation of HSP70 orchestrates its binding to and stabilization of BCL2 mRNA and renders pancreatic cancer cells resistant to therapeuticsCancer Res8045004513202010.1158/0008-5472.CAN-19-173832699135 ChuangCYChangCPLeeYJLinWLChangWWWuJSChengYWLeeHLiCPRMT1 expression is elevated in head and neck cancer and inhibition of protein arginine methylation by adenosine dialdehyde or PRMT1 knockdown downregulates proliferation and migration of oral cancer cellsOncol Rep3811151123201710.3892/or.2017.573728656289 ZhouWYueHLiCChenHYuanYProtein arginine methyltransferase 1 promoted the growth and migration of cancer cells in esophageal squamous cell carcinomaTumour Biol3726132619201610.1007/s13277-015-4098-3 ZhongJCaoRXZuXYHongTYangJLiuLXiaoXHDingWJZhaoQLiuJHWenGBIdentification and characterization of novel spliced variants of PRMT2 in breast carcinomaFEBS J279316335201210.1111/j.1742-4658.2011.08426.x OuCYLaBonteMJManegoldPCSoAYIanculescuIGerkeDSYamamotoKRLadnerRDKahnMKimJHStallcupMRA coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expressionMol Cancer Res9660670201110.1158/1541-7786.MCR-10-0223214782683096696 El MessaoudiSFabbrizioERodriguezCChuchanaPFauquierLChengDTheilletCVandelLBedfordMTSardetCCoactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 geneProc Natl Acad Sci USA1031335113356200610.1073/pnas.0605692103169388731569167 WangLZhaoZMeyerMBSahaSYuMGuoAWisinskiKBHuangWCaiWPikeJWCARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasisCancer Cell30179180201610.1016/j.ccell.2016.06.01327479032 LiuJFengJLiLLinLJiJLinCLiuLZhangNDuanDLiZArginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancerEMBO Rep21e48597202010.15252/embr.201948597 Al-DhaheriMWuJSklirisGPLiJHigashimatoKWangYWhiteKPLambertPZhuYMurphyLXuWCARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cellsCancer Res7121182128201110.1158/0008-5472.CAN-10-2426212823363076802 WangYPZhouWWangJHuangXZuoYWangTSGaoXXuYYZouSWLiuYBArginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancerMol Cell64673687201610.1016/j.molcel.2016.09.02827840030 ZakrzewiczDDidiasovaMKrügerMGiaimoBDBorggrefeTMiethMHockeACZakrzewiczASchaeferLPreissnerKTWygreckaMProtein arginine methyltransferase 5 mediates enolase-1 cell surface trafficking in human lung adenocarcinoma cellsBiochim Biophys Acta Mol Basis Dis186418161827201810.1016/j.bbadis.2018.02.02129501774 ZhangSMaYHuXZhengYChenXTargeting PRMT5/Akt signalling axis prevents human lung cancer cell growthJ Cell Mol Med2313331342201910.1111/jcmm.140366349228 RengasamyMZhangFVashishtASongWMAguiloFSunYLiSZhangWZhangBWohlschlegelJAWalshMJThe PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancerNucleic Acids Res451110611120201710.1093/nar/gkx727289774705737218 WangZKongJWuYZhangJWangTLiNFanJWangHZhangJLingRPRMT5 determines the sensitivity to chemotherapeutics by governing stemness in breast cancerBreast Cancer Res Treat168531542201810.1007/s10549-017-4597-6 BeketovaEFangSOwensJLLiuSChenXZhangQAsberryAMDengXMalolaJHuangJProtein arginine methyltransferase 5 promotes pICln-dependent androgen receptor transcription in castration-resistant prostate cancerCancer Res8049044917202010.1158/0008-5472.CAN-20-1228329990007669631 LiuMYaoBGuiTGuoCWuXLiJMaLDengYXuPWangYPRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progressionTheranostics1044374452202010.7150/thno.42047322925067150477 LiuXZhangJLiuLJiangYJiJYanRZhuZYuYProtein arginine methyltransferase 5-mediated epigenetic silencing of IRX1 contributes to tumorigenicity and metastasis of gastric cancerBiochim Biophys Acta Mol Basis Dis186428352844201810.1016/j.bbadis.2018.05.01529802960 JeonJYLeeJSParkERShenYNKimMYShinHJJooHYChoEHMoonSMShinUSProtein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cellsOncol Rep40536544201829749478 JiangHZhuYZhouZXuJJinSXuKZhangHSunQWangJXuJPRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinomaCancer Med7869882201810.1002/cam4.1360294417245852340 ChungJKarkhanisVBaiocchiRASifSProtein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/β-catenin and AKT/GSK3β proliferative signalingJ Biol Chem29476927710201910.1074/jbc.RA119.007640308859416514641 ZhuFGuoHBatesPDZhangSZhangHNomieKJLiYLuLSeiboldKRWangFPRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in lymphoma cellsLeukemia3328982911201910.1038/s41375-019-0489-6311233437494157 HuGWangXHanYWangPProtein arginine methyltransferase 5 promotes bladder cancer growth through inhibiting NF-kB dependent apoptosisEXCLI J17115711662018 AvasaralaSWuPYKhanSQYanlinSVan ScoykMBaoJDi LorenzoADavidOBedfordMTGuptaVPRMT6 promotes lung tumor progression via the alternate activation of tumor-associated macrophagesMol Cancer Res18166178202010.1158/1541-7786.MCR-19-02046942249 JiangNLiQLPanWLiJZhangMFCaoTSuSGShenHPRMT6 promotes endometrial cancer via AKT/mTOR signaling and indicates poor prognosisInt J Biochem Cell Biol120105681202010.1016/j.biocel.2019.105681 BaldwinRMHaghandishNDaneshmandMAminSParisGFallsTJBellJCIslamSCôtéJProtein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of MMP9 expressionOncotarget630133032201510.18632/oncotarget.3072256052494413634 ChengDHeZZhengLXieDDongSZhangPPRMT7 contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with HSPA5 and EEF2Onco Targets Ther1148694876201810.2147/OTT.S166412301473386098420 YangYBedfordMTProtein arginine methyltransferases and cancerNat Rev Cancer133750201310.1038/nrc3409

Protein arginine methyltransferases catalyse methylation at arginine to generate MMA, ADMA and SDMA. Arginine residues in the tails of histones may be MMA, ADMA or SDMA. The MMA form of arginine is generally regarded as an intermediate prior to the dimethylated state. This schematic was adapted from the review by Yang and Bedford (169). MMA, ω-NG-monomethylarginine; ADMA, ω-NG,NG-asymmetric dimethylarginine; SDMA, ω-NG,N'G-symmetric dimethylarginine.

Protein structure, methylation function and chromosomal location of each member of the PRMT family. A total of 9 mammalian PRMTs were identified and these have unique signatures (yellow, red, green and blue) with high sequence similarity. PRMT, protein arginine methyltransferase; MMA, monomethylarginine; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; CARM1, coactivator-associated arginine methyltransferase 1; SH3, SH3 domain; ZnF, zinc finger motif; PH, Pleckstrin homology domain; myr, myristoyl; TPR, tetratricopeptide repeat.

PRMTs methylate arginine on histones H2A, H2B, H3 and H4. PRMT5, PRMT6 and PRMT7 are able to methylate H2A. PRMT2, CARM1, PRMT5 and PRMT6 are able to methylate H3. PRMT1, PRMT3, PRMT5, PRMT6, PRMT7 and PRMT8 can methylate H4. PRMT, protein arginine methyltransferase; CARM1, coactivator-associated arginine methyltransferase 1.

Role of PRMTs in histone methylation.

Type Residues Enzymes Functions (Refs.)
H2A R3me1/me2s PRMT5 Transcriptional repression (22)
R3 PRMT7 DNA repair (23)
R29me2a PRMT6 Transcriptional repression (21)
H3 R2me1 PRMT5 Transcriptional activation (28)
R2me2a PRMT6 Transcriptional repression (112,113)
R2me1/me2s PRMT5 Transcriptional activation (29,114)
R8me2a PRMT6 Transcriptional repression (115)
R8me2a PRMT2 Transcriptional activation (24,25)
R8me2s PRMT5 Transcriptional activation and repression (33,34,116,117)
R17/R26/ R42me2a CARM1 Transcriptional activation (26)
R26me2a CARM1 Transcriptional repression (118)
R3me1 PRMT5 Transcriptional activation (42)
H4 R3me2a PRMT1 Transcriptional activation (35,41,119)
R3me2a PRMT3 Transcriptional activation (44,120)
R3 PRMT6 Transcriptional activation/ repression (121,122)
R3me2s PRMT5 Transcriptional repression, blocking of SHH pathway, promotion of DNA methylation (36-39,42,43,123)
R17me1 PRMT7 Facilitation of PRMT5-mediated H4R3me2s (124)
R19me1 PRMT7 Facilitation of PRMT5-mediated H4R3me2s (124)
R3me2a PRMT8 Transcriptional activation (125)

PRMT, protein arginine methyltransferase; CARM1, coactivator-associated arginine methyltransferase 1; SHH, Sonic hedgehog.

Role of PRMTs in nonhistone methylation.

Type Enzymes Substrate Function (Refs.)
TFs PRMT1 TWIST1 Activation of EMT (126,127)
PRMT1 TAF15 Affects TAF15 cellular localization and expression of TAF15-targeted genes (128)
PRMT1 RUNX1 Enhanced transcription activity to maintain the peripheral T-cell count (129)
PRMT1 FOXO1 Enhanced cell apoptosis and gluconeogenesis (130)
PRMT1/5 E2F-1 Transcriptional activation promotes apoptosis; increased cell viability (50,78)
PRMT1 C/EBPα Promotes cyclin D1 expression (131)
PRMT1 SMAD7 Facilitates the dissociation of Smad7 from type I receptors (55)
PRMT5 SREBP1 Increases adipogenesis and tumour growth in hepatocellular carcinoma (51)
PRMT5 BCL6 Inhibits the activity of BCL6 target genes (52)
RBPs PRMT1 PABPN1 Reduces the affinity of PABPN1 for transportin, promotes the PABPN1-RNA interaction (54,132)
PRMT1 ICP27 Nuclear foci-like structure formation, RNA-binding affinity and SRPK interactions of ICP27 (53)
PRMT5 hnRNPA1 Promotes hnRNPA1 interaction with ITAD, accompanied by translation of cyclin D1 and c-MYC (93)
DNA damage response PRMT1 53BP1 Interaction with single- and double-stranded DNA (133)
PRMT1 MRE11 Induction of the intra-S-phase checkpoint defect (134)
PRMT1 BRCA1 Influences the interaction of BRCA1 with specific promoters or proteins (135)
PRMT1/3/6 TOP3B Translational regulation (136)
PRMT6 RCC1 Chromatin binds and activates RAN (67)
RNA splicing PRMT5 Sm proteins Assembles into snRNPs (137)
PRMT5 SRSF1 Differential binding of SRSF1 to its alternative pre-mRNA splicing targets (75)
PRMT5 TIP60/KAT Ensuring error-free HR DNA repair and maintaining genomic integrity (57)
PRMT1 RBM15 Aberrant RNA splicing (138)
PRMT9 SF3B2 Maintains splicing fidelity (79)
PRMT1 EZH2 Regulates stability and promotes breast cancer metastasis (139)
Signalling pathways PRMT1 ERα Activates the cytoplasmic signalling (140)
PRMT1 EGFR Activates the EGFR signalling pathway (141)
PRMT5 P65 Activates NF-κB (82)
PRMT5 TRIM21 Activates NF-κB (83)
PRMT5 SKI Altered TGFβ signalling-mediated transcriptional regulation (86)
PRMT3 HIF1α Activation of the HIF1/VEGF signalling pathway (88)

TF, transcription factor; RBP, RNA binding protein; PRMT, protein arginine methyltransferase; EMT, epithelial to mesenchymal transition. TWIST1, twist family bHLH transcription factor 1; TAF15, TATA-box binding protein associated factor 15; RUNX1, RUNX family transcription factor 1; FOXO1, forkhead box O1; E2F-1, E2F transcription factor 1; C/EBPα, CCAAT enhancer binding protein α; SMAD7, SMAD family member 7; SREBP1, Sterol regulatory element binding protein 1; BCL6, BCL6 transcription repressor; PABPN1, poly(A)-binding protein 1; ICP27, infected cell protein 27; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; 53BP1, p53 binding protein 1; MRE11, meiotic recombination 11; BRCA1, breast cancer 1; TOP3B, DNA topoisomerase III beta; RCC1, regulator of chromosome condensation 1; RAN, ras-related nuclear protein; SRSF1, serine and arginine rich splicing factor 1; TIP60, Tat interactive protein 60kDa; KAT5, lysine acetyltransferase 5; RNM15, RNA binding motif protein 15; SF3B2, splicing factor 3b subunit 2; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; ERα, estrogen receptor alpha; EGFR, epidermal growth factor receptor; TRIM21, tripartite motif containing 21; TGFβ, transforming growth factor beta; HIF1α, hypoxia inducible factor 1 subunit alpha; VEGF, vascular endothelial growth factor.

Roles of different PRMTs in cancer.

PRMTs Cancer type Expression Biological mechanism Function (Refs.)
PRMT1 Colorectal cancer High Activation of EGFR signalling by EGFR methylation Oncogenic (35)
High Promotion of tumour growth by regulation of E2F-1 Oncogenic (50)
Breast cancer High Modulation of EMT and cellular senescence through regulation of ZEB1 Oncogenic (41)
High Methylation of EZH2 and regulation of its stability Oncogenic (139)
High Activation of cyclin D1 expression by methylation of C/EBPα Oncogenic (131)
High Regulation of IGF-1 signalling by methylation of ERα Oncogenic (142)
Pancreatic cancer High Promotion of β-catenin expression by binding the β-catenin promoter Oncogenic (90)
High Stabilisation of BCL2 mRNA by methylation of HSP70 Oncogenic (143)
Lung High Promotion of EMT by methylation of Twist1 Oncogenic (126)
HNC High Promotion of proliferation and migration Oncogenic (144)
ESCC High Promotion of the growth and migration by activating Hedgehog signalling Oncogenic (145)
PRMT2 Hepatocellular carcinoma High Acceleration of tumorigenesis by activating Bcl2 via H3R8 methylation Oncogenic (24)
Glioblastoma High Promotion of oncogenic activation and tumorigenesis by methylation of H3R8 Oncogenic (25)
Breast cancer High Splice variants of PRMT2 modulate ERα signalling Oncogenic (146)
PRMT3 Colorectal cancer High Promotion of tumorigenesis through regulating c-MYC stabilization Oncogenic (87)
High Promotion of tumorigenesis by methylating and stabilizing HIF1α Oncogenic (88)
Pancreatic cancer High Increase of ABCG2 expression by methylation of hnRNPA1 Oncogenic (92)
High Induction of metabolic reprogramming Oncogenic (107)
PRMT4 Ovarian cancer High Activation of Wnt/β-catenin and neoplastic transformation Oncogenic (147)
Breast cancer High Upregulation of cyclin E1 led to the promotion of S-phase entry Oncogenic (148)
High Enhancement of tumour progression and metastasis by methylation of BAF155 Oncogenic (149)
High Promotion of invasion and metastasis by regulation of LSD1 stability Oncogenic (150)
- Block of tumour cell proliferation and induction of differentiation through ERα-regulated genes Tumour suppressive (151)
Pancreatic cancer Low Inhibition of glutamine metabolism and tumour growth by methylation of MDH1 Tumour suppressive (152)
Liver cancer Low Regulation of glucose metabolism by GAPDH methylation Tumour suppressive (152)
PRMT5 Lung cancer High SHARPIN-PRMT5-H3R2me1 axis activates transcription of metastasis-related genes Oncogenic (28)
High Enhancement of localization to the surface membrane by Enolase-1 methylation Oncogenic (153)
High Promotion of tumour cell proliferation by regulation of AKT Oncogenic (154)
Breast cancer High Critical regulator of breast cancer stem cells via histone methylation and Foxp1 expression Oncogenic (29)
High PRMT5/WDR77 complex regulates alternative splicing through ZNF326 Oncogenic (155)
High Increase of sensitivity to chemotherapeutics by governing stemness Oncogenic (156)
Prostate cancer High Promotion of pICln-dependent androgen receptor transcription Oncogenic (157)
Gastric cancer High PRMT5-dependent transcriptional repression of c-MYC target genes Oncogenic (158)
High Mediation of epigenetic silencing of IRX1 contributes to tumorigenicity and metastasis Oncogenic (159)
AML High Genetic deletion or small-molecule inhibition Oncogenic (36)
High Gene activation and repression via histone arginine methylation Oncogenic (117)
HCC High Promotion of invasive activity of tumour cells by regulation of MMP2 Oncogenic (160)
High Promotion of tumour cell proliferation by inhibiting BTG2 expression via the ERK signalling pathway Oncogenic (161)
Melanoma High Regulation of MDM4 via alternative splicing result in response to CDK4/6 inhibitors Oncogenic (77)
Lymphoma High Activation of WNT/β-catenin and AKT/GSK3β signalling Oncogenic (162)
DLBCL High PRMT5 is upregulated by B-cell receptor signalling and forms a positive feedback loop with PI3K/AKT Oncogenic (163)
Bladder cancer High Promotion of cancer growth through inhibiting NF-κB-dependent apoptosis Oncogenic (164)
PRMT6 Lung cancer High Activation of tumour-associated macrophages via interaction with ILF2 Oncogenic (165)
Endometrial cancer High Activation of AKT/mTOR signalling Oncogenic (166)
PRMT7 Breast cancer High Promotion of tumour cell invasion through the induction of MMP9 expression Oncogenic (167)
NSCLC High Contribution to tumour cell metastasis by the interaction with HSPA5 and EEF2 Oncogenic (168)
PRMT9 HCC High Promotion of tumour cell invasion and metastasis by activating PI3K/Akt/ GSK-3β/Snail signalling Oncogenic (85)

AML, acute myeloid leukemia; HNC, head and neck cancer; DLBCL, diffuse large B-cell lymphoma; ESCC, esophageal squamous cell carcinoma; NSCLC, non-small cell lung carcinoma; HCC, hepatocarcinoma; PRMT, protein arginine methyltransferase; EGFR, epidermal growth factor receptor; E2F-1, E2F transcription factor 1; EMT, epithelial to mesenchymal transition; ZEB1, Zinc finger E-box binding homeobox 1; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; C/EBPα, CCAAT enhancer binding protein alpha; IGF-1, IGF like family member 1; ERα, estrogen receptor alpha; BCL2, BCL2 apoptosis regulator; HSP70, heat shock protein 70; ABCG2, ATP binding cassette subfamily G member 2; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; BAF155, SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1; LSD1, lysine demethylase 1; MDH1, malate dehydrogenase 1; SHARPIN, SHANK-associated RH domain interactor; WDR77, WD repeat domain 77; ZNF326, zinc finger protein 326; IRX1, iroquois homeobox 1; MMP2, matrix metallopeptidase 2; BTG2, BTG anti-proliferation factor 2; ILF2, interleukin enhancer binding factor 2.