Effects of m6A modifications on signaling pathways in human cancer (Review)

  • Authors:
    • Fangyuan Liu
    • Xiulan Su
  • View Affiliations

  • Published online on: February 19, 2021     https://doi.org/10.3892/or.2021.7987
  • Article Number: 36
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

N6‑methyladenosine (m6A) is one of the most prevalent post‑transcriptional RNA modifications. The enzymes involved in the regulation of m6A include methyltransferase (writers), demethylase (erasers) and m6A recognition proteins (readers). Accumulating studies have demonstrated that m6A modifications have a distinct effect on various biological processes, including tumorigenesis, cell differentiation, embryonic development and neurogenic diseases, while our knowledge of the specific mechanism underlying m6A methylation in various cancer types is still limited. Various signaling pathways have an effect on tumorigenesis, invasion and apoptosis of malignant tumors. The present review summarizes the recent progress in research regarding the role of m6A in human cancer and discusses the influence of m6A on classic signaling pathways in malignant tumors.

Introduction

As an essential part of the central dogma of molecular biology, mRNA and other forms of RNA serve crucial roles in biological systems by passing on genetic information. Although research on chemical modifications of RNAs began in 1965 (1), there is limited knowledge regarding the underlying regulatory mechanisms of RNA modifications in biological processes. According to the MODOMICS database (https://iimcb.genesilico.pl/modomics), 172 different RNA chemical modifications, such as 5-methylcytosine, 1-methylguanosine, N6-methyladenosine (m6A) and N1-methyladenosine, have been observed in all organisms at present. Among these modifications, m6A methylation is considered the most abundant and conserved internal transcriptional modification (2). Research on m6A methylation has been limited in the past due to a lack of accurate detection methods; however, with the development of high-throughput m6A sequencing methods (3), the understanding of the biological functions of m6A has advanced.

The process of m6A methylation is regulated by several enzymes, including writers, erasers and readers (Fig. 1) (4,5). Writers promote the formation of m6A (68), erasers specifically remove the methylated group from mRNAs, and readers recognize and bind m6A modifications to exert biological functions (9,10). The observation of the demethylation functions of fat mass and fat mass and obesity-associated protein (FTO) (11), and alkB homologue (ALKBH)5 (12) as an eraser, demonstrated that m6A methylation is a dynamic and reversible process. Malignant tumors are a group of abnormal cells with distinctly different functions and gene expression compared with normal cells. Research on the mechanisms of m6A in cancer has recently advanced due to improvements in the understanding of the roles of m6A in post-transcriptional modifications (4). The present review summarizes the molecular functions and mechanisms of m6A and its three regulators in human cancer, and discusses their roles in the regulation of malignant tumor signaling pathways.

Brief overview of the history of m6A

Since its discovery in the 1970s, m6A has been the most prevalent modification in polyadenylated mRNAs (2). It has been estimated to be present in three m6A residues per mRNA on average (13). Since it is ubiquitous in nature, m6A can be found in yeast (14), fruit flies (15), mammals (2,16) and bacteria (17). Since m6A can undergo reverse transcription to form thymine and cannot be detected by chemical modifications, transcriptome-wide mapping of m6A remains difficult (18). In 2012, a high-throughput sequencing method based on antibodies was developed by two independent groups to map m6A distribution in the entire RNA sequence, which improved the detection efficiency of m6A (3,19).

It was originally hypothesized that the process of m6A was static; however, in 2011, FTO (11) and ALKBH5 (12) were demonstrated to be able to function as demethylases, indicating that the process of m6A is reversible. Subsequently, various proteins, including Vir like m6A methyltransferase associated (VIRMA) (8,16), insulin like growth factor 2 (IGF2BP) (10) and heterogeneous nuclear ribonucleoprotein (7), were demonstrated to function as writers and readers.

Readers, writers and erasers in m6A methylation

It is well-known that writers and erasers regulate m6A via methylation and demethylation, respectively (5,20,21). Furthermore, m6A groups exert biological functions by being recognized by readers, which are a type of specific binding protein (22,23).

In mammals, writers catalyze the methylation of m6A in the form of a methyltransferase complex consisting of methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14) (7) and Wilms' tumor 1-associating protein (WTAP) (7). METTL14 has a greater effect on m6A than METTL3 although their proportion in the complex is 1:1 (7). Previous studies have identified more writers, including methyltransferase-like protein 16 (METTL16) (24,25), zinc finger CCCH domain-containing protein 13 (ZC3H13) (26), VIRMA (8,16) and RNA-binding motif protein 15 (RBM15) (27). METTL16 is a methyltransferase which binds to the conserved U6 small nuclear RNA, non-coding RNA and precursor messenger RNA, and is involved in regulating intracellular homeostasis and mRNA splicing in response to intracellular S-adenosyl-L-methionine levels (24,25). VIRMA (also referred to as KIAA1429) can promote m6A modification and knockdown of VIRMA, resulting in a more conspicuous decrease of m6A content than the effect of METTL3 and METTL14 knockdown in A549 cells (8). RBM15 catalyzes m6A modification by binding to the U-rich region in long non-coding RNA X inactive specific transcript (27). In addition, ZC3H13 has been identified as a novel m6A writer in mice and Drosophila (26). The first eraser was identified in 2011 by Jia et al (11), who revealed that FTO could demethylate m6A. ALKBH5 was identified as the second eraser (12) as it demethylates m6A in a different way compared with FTO. The two intermediates, N6-hydroxymethyladenosine and N6-formyladenosine are first oxidized by FTO during the process of demethylation, while ALKBH5 catalyzes the direct removal of m6A (12,28). Readers can identify m6A modifications and bind to methylated RNA to transfer biological signals to downstream signaling pathways (21,22). Proteins containing the YT521-B homology (YTH) domain, such as the YTH domain-containing family (YTHDF) proteins, have been classed as readers (9). Notably, these recognition proteins of m6A exhibit distinct mechanisms. For example, Wang et al (29) reported the translation-promoting role of YTHDF1 and the mRNA-destabilizing role of YTHDF2. By interacting with initiation factors, including IGF2BP1 and stress granule assembly factor 1, YTHDF1 enhances the translation efficiency of target RNAs and ensures efficient protein expression from these shared transcripts. By contrast, YTHDF2 accelerates the degradation of m6A-modified transcripts to control the lifetime of the methylated transcripts (29,30). YTHDF3 serves as a hub to regulate the RNA accessibility of YTHDF1 and YTHDF2 (31).

m6A regulation of biological processes

m6A is widely expressed in eukaryotes and serves a crucial role in the regulation of various biological processes. In mammals, m6A modifications affect development (12), metabolism (11,3234) and immunity (3537). Furthermore, previous studies have indicated that m6A has effects on stem cell differentiation (38,39), human metabolic diseases (40), viral infections (4144) and inflammation (45).

m6A is involved in the regulation of pluripotency and differentiation of stem cells

Pluripotent mouse embryonic stem cells (mESCs) undergo two different states during differentiation, naive and primed (46). m6A modifications serve key roles in the regulation of pluripotency during the transition from the naive state to the primed state (38). METTL3 depletion has a different effect on naïve and primed pluripotent stem cells. The depletion of METTL3 in naïve cells blocks differentiation and amplifies the highly expressed naïve pluripotency genes, which boosts naïve circuitry stability (38). When METTL3 and m6A are inhibited in epiblast stem cells, which are in a primed state, the expression levels of pluripotent genes are reduced, whereas the expression levels of lineage commitment markers are increased (38). By knocking out METTL3, Geula et al (38) revealed m6A as a timely maintainer of the balance between pluripotency and lineage priming factors, thus ensuring the orderly differentiation of mESCs. However, Batista et al (47) reported that the deletion of METTL3 maintains the self-renewal capacity of mESCs and mouse embryonic fibroblasts. These contradictory results may be due to the cell state. For example, different transcripts are expressed and methylated in naïve and primed embryonic stem cells (ESCs) (48). Therefore, METTL3 inactivation regulates the expression levels of genes that affect cell fate and identity, and this activity maintains pluripotency in naïve stem cells but promotes differentiation in primed stem cells (38).

YTH domain containing 1 (YTHDC1) is a known m6A reader found in the nucleus (49). Similar to METLL3, the inactivation of YTHDC1 is embryonic lethal, which demonstrates that YTHDC1 is required for the development of mitotic spermatogonia in males and postnatal oocyte growth in females (50). Notably, when cytoplasmic YTHDF1and YTHDF2 are depleted, ESCs cannot emerge from diversification (50), indicating that the YTHDC1-mediated regulation of ESC differentiation occurs in the nucleus rather than in the cytoplasm.

Other erasers and readers of m6A have also been demonstrated to regulate the development and differentiation of ESCs. Knocking out YTHDF2 enhances the proliferation of mouse and human hematopoietic stem cells, highlighting its potential role in transplantation-related applications (51). Notably, m6A modification has not only been demonstrated to regulate differentiation in ESCs (38), but also in developmental cancer cells (52). Lobo et al (52) revealed that abundance of m6A and expression of its writer VIRMA/reader YTHDF3 are different among testicular germ cell tumor (TGCT) subtypes, with higher levels in seminomas. Higher VIRMA and YTHDF3 mRNA levels in seminomas maintain a low differentiation level compared with teratoma, which represents more differentiated TGCTs. However, Lobo et al (52) observed a stronger m6A immunostaining intensity in teratoma, suggesting that other writers may be responsible for establishing m6A in teratoma and/or that m6A modification may target other RNAs and even impart them a different fate.

m6A regulates biological metabolism

m6A is involved in metabolism and regulation of metabolic genes. It has been demonstrated that the demethylase FTO is involved in the metabolism of glucose and lipids in mammals (33,40). As a classic target of fat metabolism, FTO can induce mRNA expression of FOXO1, glucose-6-phosphatase catalytic subunit and diacylglycerol O-acyltransferase 2, and is closely associated with glucose metabolism in type 2 diabetes (40). FTO has also been demonstrated to regulate the expression levels of activating transcription factor 4 to control glucose production in the liver (53). Wu et al (54) demonstrated that FTO modulates the deposition of triglycerides and the accumulation of lipids by regulating the m6A-YTHDF2 signaling pathway. At present, the specific sites and complete mechanisms in glucose or fat production are unknown, and thus, future studies are required to address this.

m6A controls various aspects of immunity

Researchers have highlighted the roles of m6A in anti-inflammatory immunity, antitumor immunity and adaptive immunity (36,37). Yu et al (45) have demonstrated that YTHDF2 is involved in the inflammatory response of macrophages. Knockdown of YTHDF2 markedly increased the expression levels of IL-6, TNF-α and IL-12, which were induced by lipopolysaccharide, and the phosphorylation levels of p65, p38 and ERK1/2 in macrophages were also upregulated. Furthermore, silencing of YTHDF2 could induce upregulation of mitogen-activated protein kinase 4 and mitogen-activated protein kinase 4 by stabilizing mRNA, activating MAPK and NF-κB signaling pathways, and this aggravates the inflammatory response in macrophages. Liu et al (55) reported that YTHDF2 recognized and degraded, long non-coding RNA Dpf3 in dendritic cells specifically, which markedly inhibited C-C motif chemokine receptor 7-mediated dendritic cell migration and contributed to inflammatory responses. Studies of the m6A-induced effect on antitumor immunity are emerging and still in their infancy. Han et al (56) demonstrated that the antigen-specific CD8+ T cell antitumor response was improved in YTHDF1-deficient mice compared with mice in the wild-type group. Blocking programmed death-ligand 1 could promote tumor regression in YTHDF1-deficient mice (57). In addition, the mechanisms by which m6A regulates adaptive immunity is an emerging field of investigation (58). Li et al (58) first elucidated the function of m6A in CD4+ T helper cells. The result suggested that deletion of METTL3 in mouse T cells disrupted T cell homeostasis and differentiation. The mRNAs of the suppressor of cytokine signaling (SOCS) family, which are involved in STAT signaling, exhibit slower mRNA decay and increased expression levels in Mettl3-deficient naïve T cells (58). This increased SOCS family activity consequently inhibits IL-7 mediated STAT5 activation and T cell homeostatic proliferation and differentiation (58).

m6A in infectious diseases

m6A modifications are involved in viral infections. Human immunodeficiency virus type 1 (HIV-1) RNA is methylated by m6A in infected cells, and readers, including YTHDF1-3, bind to methylated HIV-1 RNA to inhibit viral reverse transcription and translation (41,42). Partial knockout of m6A writers decreases HIV-1 Gag synthesis and viral release, whereas knockout of FTO has the opposite effect (42). This indicates that m6A can enhance HIV-1 protein synthesis and viral release, thereby contributing to the infection. Additionally, the proteins regulated by m6A are known to modulate the life cycle of hepatitis C virus (HCV) (43). Depletion of METTL3 and METTL14 can increase the levels of HCV infection by promoting infectious viral particle production without affecting viral RNA replication (43,59). By contrast, inhibition of the m6A demethylase FTO, but not ALKBH5, has the opposite effect (26). Furthermore, m6A has been demonstrated to serve important roles in other Flaviviridae, such as Zika virus (44). Lichinchi et al (44) revealed that the depletion or overexpression of the RNA methyltransferase could impact viral replication, demonstrating that the host RNA methyltransferase machinery acts as a key post-transcriptional regulator of Zika virus. Furthermore, YTHDF proteins binding to Zika RNA indicates another regulatory aspect of m6A readers, which serves a role in viral RNA metabolism (44). Both RNA modification layers may act as pro- or anti-viral factors in the host (44).

In addition, m6A serves a critical regulatory role in inflammation (60,61), gametogenesis (62,63) and nervous system development (64,65). Importantly, the immune regulatory role of m6A may provide a novel idea for cancer immunotherapy research.

Role of m6A modifications in cancer

Consistent with the regulation of m6A modifications in normal biological processes, m6A is associated with a variety of human cancer types. However, the catalysis of m6A in cancer is not unitary. Numerous studies have demonstrated that m6A serves an important role in various cancers, often via the actions of regulators that influence m6A modifications and expression of oncogenes or tumor suppressor genes. The special roles of m6A regulators in human cancer types are summarized in Table I; however, the mechanisms by which m6A regulators contribute to carcinogenesis remain to be elucidated. The present review summarizes how the three types of m6A regulatory proteins function in human cancer and discusses the role of m6A in several classic signaling pathways.

Table I.

Tumor-suppressing and tumor-promoting roles of m6A regulators in human cancer types.

Table I.

Tumor-suppressing and tumor-promoting roles of m6A regulators in human cancer types.

First author, yearm6A regulatorType of cancerRole in cancerMechanism(Refs.)
Vu et al, 2017METTL3AMLOncogenePromotes the translation of c-MYC, BCL2 and PTEN mRNA(68)
Chen et al, 2019 BCOncogeneMETTL3-mediated m6A modification operates a regulatory network which involves AFF4/NF-κB/MYC to promote BC progression(118)
Shen et al, 2020 CRCOncogeneActivates glycolysis and enhances colorectal cancer progression(72)
Li et al, 2019 GBMOncogeneModulates mediated mRNA decay of splicing factors and alternative splicing isoform switches(119)
Yue et al, 2019 GCOncogeneEnhances ZMYM1 mRNA stability and facilitates the EMT program and metastasis(70)
Yang et al, 2020 GCOncogeneMediates MYC target genes, and promotes proliferation and migration(71)
Chen et al, 2020 HCCOncogeneInhibits SOCS2 mRNA expression, and reduces HCC cell proliferation, migration, and colony formation(73)
Wang et al, 2020 THCAOncogeneRegulates methylation of TCF1 mRNA and the activated Wnt signaling pathway(120)
Weng et al, 2018METTL14AMLOncogeneRegulates MYB and MYC mRNA via m6A modification(121)
Ma et al, 2017 HCCSuppressorInteracts with DGCR8 and positively modulates the primary microRNA-126 process(67)
Cui et al, 2017 GBMSuppressorSuppresses glioblastoma stem cell proliferation and self-renewal(84)
Bansal et al, 2014WTAPAMLOncogenePromotes proliferation and arrests differentiation of leukemia cells(122)
Chen et al, 2019 HCCOncogeneFacilitates progression of HCC via m6A-HuR-dependent epigenetic silencing of ETS1(123)
Qian et al, 2019VIRMABCOncogenePromotes BC progression by modulating CDK1(80)
Cheng et al, 2019 HCCOncogenePromotes the migration and invasion of HCC by altering m6A modification of ID2 mRNA(124)
Li et al, 2017FTOAMLOncogeneRegulates expression of targets, such as ASB2 and RARA, by reducing m6A levels, and enhances leukemic oncogene-mediated cell transformation and leukemogenesis(81)
Xu et al, 2017 GCOncogeneUnclear(125)
Li et al, 2019 LCOncogenePromotes the proliferation of LC cells by regulating USP7 mRNA(126)
Li et al, 2019 HCCOncogeneTriggers the demethylation of PKM2 mRNA and accelerates translation(127)
Zhang et al, 2017ALKBH5GBMOncogeneMaintains tumorigenicity by sustaining FOXM1 expression(86)
Chao et al, 2020 LCOncogeneAffects the proliferation and invasion of LC cells by downregulating m6A modification of FOXM1 mRNA(128)
Lin et al, 2019YTHDF1HCCOncogeneMediates m6A-increased translation of Snail mRNA(129)
Nishizawa et al, 2019 CRCOncogeneInduces the translation of m6A-modified FZD9 and Wnt6 mRNA(88)
Mapperley et al, 2021YTHDF2AMLSuppressorSuppresses proinflammatory signaling pathways and sustains hematopoietic stem cell function(60)
Li et al, 2020 PCOncogeneMediates the mRNA degradation of the tumor suppressors LHPP and NKX3-1(130)
Dixit et al, 2020 GBMOncogeneStabilizes oncogene MYC and VEGFA transcripts in glioblastoma stem cells(131)
Chang et al, 2020YTHDF3BRCOncogeneEnhances the translation of ST6GALNAC5, GJA1 and EGFR, associated with brain metastasis(132)
Ma et al, 2020YTHDC2LCSuppressorInhibits LC tumorigenesis by suppressing SLC7A11-dependent antioxidant function(133)
Wu et al, 2019hnRNPCRCOncogenem6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1(134)

[i] Tumor-suppressing and tumor-promoting roles of m6A regulators in different human cancer types are shown. This illustrates the different effects of m6A regulators and their mechanisms. m6A, N6-methyladenosine; AML, acute myeloid leukemia; BC, bladder cancer; BRC, breast cancer; CRC, colorectal cancer; GBM, glioblastoma; GC, gastric cancer; HCC, hepatic cell carcinoma; LC, lung cancer; PC, prostate cancer; THCA, thyroid carcinoma.

Methyltransferases/writers in cancer

Writers positively regulate m6A modifications. The aberrant expression of writer proteins in tumors affects oncogenes and tumor suppressors, thus influencing tumorigenesis (66), invasion (66) and metastasis (67). Interestingly, the mechanisms of writers in different types of cancer are not uniform. METTL3 is highly expressed in acute myeloid leukemia (AML) (68), and contributes to the translation of oncogenes. In gastrointestinal cancer, METTL3 has been demonstrated to be closely associated with the processes involved in the progression of cancer, including tumor cell proliferation, apoptosis, metastasis, angiogenesis and cancer stem cell maintenance (69). A number of studies have demonstrated that METTL3 generally acts as an oncogene in gastrointestinal cancer types, such as gastric cancer (GC) (70,71), colorectal cancer (CRC) (72), hepatocellular carcinoma (HCC) (73) and pancreatic cancer (74,75). Furthermore, the modified mRNA targets of METTL3 are diverse. For example, METTL3-mediated m6A modification can increase the expression levels of mRNA targets, including zinc finger MYM-type containing 1 (ZMYM1) (70), SEC62 homolog, preprotein translocation factor (76) and MYC (71), in a way of enhancing mRNA stability in GC, and promotes tumor cell proliferation, migration and invasion. Similarly, other writers, including METTL16 (24,25), ZC3H13 (26), VIRMA (8,16) and RBM15 (27), have been reported to have a complicated effect in other malignancies, such as hepatocellular carcinoma (77), colorectal cancer (78), prostate cancer (79) and breast cancer (80). It was hypothesized that induction mechanisms other than m6A regulation cause this phenomenon.

Demethylases/erasers in cancer

Increasing numbers of studies of erasers in cancer are being performed. These studies have identified that the m6A demethylase, FTO, serves a critical oncogenic role in AML (57,81,82). Specifically, its high expression in AMLs with mixed lineage leukemia rearrangements and fms related receptor tyrosine kinase 3-internal tandem duplication and/or nucleophosmin 1 mutations is associated with increased tumorigenesis and invasion of AML cells (81). Enhancing the expression levels of FTO can reduce the levels of m6A and mRNA transcription of ankyrin repeat and SOCS box containing 2 (ASB2) and retinoic acid receptor α (RARA) (81). ASB2 and RARA are known to regulate the differentiation of leukemia cells by inhibiting all-trans retinoic acid (81). In addition, FTO serves a crucial role in cholangiocarcinoma (83) and glioblastoma stem cells (84). In contrast to FTO, an AML study based on The Cancer Genome Atlas (TCGA) has suggested that ALKBH5, another m6A demethylase, exhibits frequent copy number loss that results in non-carcinogenic effects in AML (85). Furthermore, Zhang et al (86) demonstrated that ALKBH5 methylated FoxM1 to maintain proliferation and development in glioblastoma stem-like cells.

Readers in cancer

The characterization of m6A readers has provided valuable insight into to the mechanisms of m6A-mediated post-transcriptional gene regulation in cancer. It has been demonstrated that YTHDF1 is expressed at higher levels in CRC tissues, and that it contributes to malignant phenotypes and poor patient prognosis (87). A further study has indicated that YTHDF1 is induced by the oncogene c-MYC, and high YTHDF1 expression in malignant tumors can enhance the resistance to anticancer drugs, including oxaliplatin and fluorouracil (88). As another member of the YTH domain-containing family, YTHDF2 recognizes m6A modifications in the cytoplasm (31). A previous study has identified that YTHDF2 could directly bind to the 3′ end of the SOCS2 transcript, and that knockdown of YTHDF2 augmented SOCS2 expression in HCC cells (73). The SOCS family of proteins are essential tumor suppressors in different cancer types, suggesting an important role of YTHDF2 in human cancer (73). YTHDC2 is known to promote the mRNA translation of hypoxia inducible factor α1 (HIF-1α) to induce the metastasis of CRC (89). Knockdown of YTHDC2 attenuates the protein expression of metastasis-related genes, such as HIF-1α, and inhibits the metastasis in vitro and in vivo (89). IGF2BP has been demonstrated to be highly expressed in a variety of malignant tumors, such as HCC, cervical cancer and AML (10,90). Huang et al (90) reported that IGF2BP has a positive effect on the stability and translation levels of c-MYC, indicating the potential latent relationship between IGF2BP and other readers.

m6A modifications in classic signaling pathways of cancer

As more research on m6A in cancer is being conducted, several studies have examined whether m6A can regulate cancer by affecting signaling pathways, and explored the specific mechanisms of m6A. As a result, studies have demonstrated that m6A can promote or inhibit malignant tumors by regulating different signaling pathways (Figs. 2 and 3).

Wnt signaling pathway

Wnt signaling is a pivotal regulatory signaling pathway that has diverse roles in cancer progression. The m6A modification targeting Wnt signaling has been a focus of cancer research. According to a study conducted by Zhang et al (91), the Wnt signaling pathway is activated after the levels of m6A are reduced by inhibiting METTL14 in GC. By contrast, FTO knockout exhibits the opposite effect on the Wnt signaling pathway (91). This suggests that m6A can affect the activity of the Wnt signaling pathway in GC. Similarly, E-cadherin is modulated by m6A; however, more studies are required to improve the understanding of these mechanisms (92). In endometrial cancer, FTO promotes tumor metastasis and invasion (93). FTO catalyzes demethylation modification in the 3′-untranslated region (3′-UTR) of HOXB13 mRNA, thereby inhibiting m6A modification recognition by the YTHDF2 protein (93). This leads to decreased HOXB13 mRNA decay and increased HOXB13 protein expression and activation of the Wnt signaling pathway (93). Enhanced m6A modification is also considered to be an oncogenic mechanism in hepatocellular carcinoma; METTL3 expression is upregulated and Wnt/β-catenin signaling pathway activity is induced via promotion of catenin β1 expression, which ultimately accelerates hepatocellular carcinoma development (94). The Wnt signaling pathway activates several cancer-related markers, including key regulators of the cell cycle, proliferation, invasion, angiogenesis and drug resistance (95). Therefore, examining the effect of m6A on the Wnt signaling pathway will provide guidance to explore the detailed mechanisms in cancer.

Epithelial-mesenchymal transition (EMT) signaling pathway

The EMT signaling pathway is a hot spot for cancer research due to its role in the initial process of tissue carcinogenesis. Furthermore, the markers of EMT are closely associated with tumor progression processes, such as migration, invasion, proliferation, anti-apoptosis, stemness and tumor radio/chemosensitivity of cancer cells (96,97). Yue et al (70) revealed the METTL3-mediated m6A modification process in GC cells and identified ZMYM1 as a target of METTL3. The elevated expression levels of ZMYM1 repress the activation of E-cadherin promoter by recruiting C-Terminal Binding Protein/Human lysine specific demethylase l/CoREST complex, thus facilitating the EMT process. YTHDF2 is highly expressed in various cancer types and is involved in dual regulation (60,98). In pancreatic cancer, YTHDF2 knockdown increases the expression levels of YAP, which is a key protein of the TGF-β/Smad signaling pathway (98). A previous study has demonstrated that there are two m6A sites in YY1 associated protein 1 (YAP), which suggests that YTHDF2 directly binds to YAP mRNA to decrease the stability of mRNA and regulate EMT via YAP signaling inhibition (98). Progress has also been achieved in the development of novel drug targets based on m6A modifications. Chen et al (99) reported that simvastatin induced METTL3 downregulation in lung cancer tissues, which further influenced EMT via m6A modification on EZH2 mRNA and inhibited the malignant progression of lung cancer.

PI3K/Akt signaling pathway

The PI3K/Akt signaling pathway is important for cancer progression. Although aberrant activity of the PI3K/Akt signaling pathway could be associated with tumorigenesis, it also has a great impact on the proliferation, adhesion, invasion and angiogenesis of malignant tumors (100). Increasing evidence suggests that m6A modification is involved in carcinogenesis by targeting the PI3K/Akt signaling pathway (101105). In renal cell carcinoma, METTL3 inhibits the PI3K/Akt/mTOR signaling pathway and serves a role as a tumor suppressor gene (101). Zhao et al (102) conducted an analysis for sequencing data of gastrointestinal cancer from TCGA and Gene Expression Omnibus, and demonstrated that m6A modification directly modulates PI3K/Akt and mTOR signaling pathway activity by regulating critical kinases in human gastrointestinal cancer. This conclusion was supported and validated by a study by Chen et al (103). According to Chen et al (103), knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression, whereas METTL14-mediated SOX4 mRNA degradation stimulated PI3K/Akt signaling and inhibited CRC malignant process. A study revealed that m6A modification can affect the activity of the PI3K/Akt signaling pathway by regulating miRNA (104). Bi et al (104) demonstrated that METTL3 promoted miR-126-5p maturation by modifying pri-miR-126-5p in ovarian cancer. METTL3 knockdown inhibits the effect of miR-126-5p to upregulate PTEN, which prevents PI3K/Akt/mTOR signaling pathway activation. Furthermore, Liu et al (105) demonstrated that reductions of m6A methylation mediated by METTL14 mutation or reduced expression levels of METTL3 lead to the activation of the Akt signaling pathway by decreasing PHLPP2 expression and increasing mTORC2 expression, which promotes cell proliferation in endometrial cancer.

ERK signaling pathway

The ERK signaling pathway has been demonstrated to be important for cancer progression. The substrates of ERK signaling are broad, which make ERKs key regulators of proliferation, migration, apoptosis and chemo-immune-resistance, as well as appealing therapeutic targets in cancer (106). Zhong et al (107) revealed that YTHDF2 directly bound to the m6A modification site of the EGFR 3′-UTR to promote the degradation of EGFR mRNA in HCC cells, and this mechanism suppressed MEK and ERK activation, cell proliferation and tumor growth. However, previous studies, have revealed the interaction between m6A modification and the ERK signaling pathway (108,109). Xie et al (109) demonstrated that basic leucine zipper ATF-like transcription factor 2 (BATF2) could bind to p53 and enhanced its protein stability, thereby inhibiting the phosphorylation of ERK in GC, and m6A modification mediated by METTL3 could repress BATF2 mRNA expression, which provides potential prognostic and therapeutic targets for GC treatment. Conversely, the ERK signaling pathway has been demonstrated to have a positive effect on m6A deposition (108). Sun et al (108) demonstrated that ERK could phosphorylate METTL3 at S43/S50/S525 and WTAP at S306/S341, thus stabilizing the m6A methyltransferase complex in ESC and malignant tumor cells.

Other signaling pathways in cancer

In addition to the aforementioned representative signaling pathways, researchers have reported that m6A modification also serves a crucial role in other classic signaling pathways. Ghazi et al (110) investigated the effects of fusaric acid on p53 expression and its epigenetic regulation via promoter methylation and m6A modification in HCC cells. The results revealed that fusaric acid epigenetically decreased p53 expression by altering its m6A modification (110). Similarly, Ding et al (111) reported that lipopolysaccharides stimulation promotes GNAS complex locus (GNAS) expression by increasing the m6A methylation levels of GNAS mRNA, thus inducing HCC cell proliferation and invasion by interacting with the STAT3 signaling pathway in HCC. In addition, Zhang et al (112) demonstrated that β-estradiol can accelerate FTO nuclear localization and increase the proliferation of endometrial cancer cells by modulating the mTOR signaling pathway; however, the mechanism by which estrogen receptor-α mediates FTO nuclear accumulation is unclear (113).

Therapeutic implications of m6A in cancer

At present, m6A modification is mechanistically linked to the progression and prognosis of several types of cancer. Given the complicated process of m6A catalysis in cancer, m6a and its regulatory proteins may be novel therapeutic targets for cancer diagnosis and prognosis. For example, METTL3 has been considered as an oncogenic factor in numerous human types of cancer. According to recent studies, METTL3 may be an independent prognostic factor for patients with GC (114), CRC (115) and HCC (73). Similarly, evidence also supports the proliferative roles of FTO in cancer (81). FB23-2, a promising FTO inhibitor, has been demonstrated to negatively regulate proliferation and progression of human AML cell lines by inhibiting FTO (57). Furthermore, R-2HG, another small-molecule inhibitor of FTO, exhibits anticancer activity in AML (18). Additionally, clinical data have demonstrated that the expression levels of ALKBH1 are negatively associated with tumor size and TNM stage, and that the expression levels of FTO are associated with improved overall survival in patients with GC (116). Despite extensive efforts being devoted to study m6A in cancer, a number of issues associated with the function and mechanism of m6A remain unknown. Considering that novel m6A readers and writers are constantly emerging, m6A-mediated biological functions require further exploration. Additionally, multifarious modification targets and sites suggest that the specific mechanisms of m6A is not unitary even in the same type of malignant tumor. This should be clarified. The rapid development of detection methods and several novel inhibitors of m6A-related factors will provide practical assistance for researchers.

Conclusion

Increasing studies suggest that m6A is deeply involved in the regulation of gene expression. m6A can determine the fate during development and differentiation, and aberrant m6A modifications can affect classic signaling pathways, including the PI3K/AKT (91,101,105,112), Wnt (91,92) and mTOR (101,113) signaling pathways, in cancer. The dual role of m6A regulation in cancer is unclear, and may be due to differences in cell types and states. At present, m6A is gaining attention in cancer research, and may provide promising targets for cancer therapies. Future research may focus more on the specific mechanism of m6A methyltransferases and demethylases, or the specificity and sensitivity of readers. The regulatory role of m6A modification in cancer is described as a ‘double-edged sword’ implying that clinical applications require further investigation (117). Furthermore, the development of methods for the detection and analysis of m6A is required to improve the understanding of the underlying mechanisms.

Acknowledgements

Not applicable.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (grant no. 81660468).

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors' contributions

FL searched the literature and drafted the manuscript for the study. FL designed the figures. XS and FL revised the manuscript and assessed all the raw data. XS and FL are responsible for confirming the authenticity of the data. All authors read and approved the final manuscript.

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.

Glossary

Abbreviations

Abbreviations:

ALKBH5

alkB homologue 5

AML

acute myeloid leukemia

CRC

colorectal cancer

EMT

epithelial-mesenchymal transition

FTO

fat mass and obesity-associated protein

GC

gastric cancer

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HIF-1α

hypoxia inducible factor α1

HIV-1

human immunodeficiency virus type 1

IGF2BP

insulin like growth factor 2 mRNA binding proteins

m6A

N6-methyladenosine

mESC

mouse embryonic stem cell

METTL3

methyltransferase-like 3

METTL14

methyltransferase-like 14

METTL16

methyltransferase-like protein 16

RBM15

RNA-binding motif protein 15

TCGA

The Cancer Genome Atlas

TGCT

testicular germ cell tumor

VIRMA

Vir like m6A methyltransferase associated

WTAP

Wilms' tumor 1-associating protein

YTH

YT521-B homology

YTHDF

YTH domain-containing family

ZC3H13

zinc finger CCCH domain-containing protein 13

ZMYM1

zinc finger MYM-type containing 1

References

1 

Holley RW, Everett GA, Madison JT and Zamir A: Nucleotide sequences in the yeast alanine transfer ribonucleic acid. J Biol Chem. 240:2122–2128. 1965. View Article : Google Scholar : PubMed/NCBI

2 

Desrosiers R, Friderici K and Rottman F: Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA. 71:3971–3975. 1974. View Article : Google Scholar : PubMed/NCBI

3 

Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, et al: Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 485:201–206. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Yang Y, Hsu PJ, Chen YS and Yang YG: Dynamic transcriptomic m(6)A decoration: Writers, erasers, readers and functions in RNA metabolism. Cell Res. 28:616–624. 2018. View Article : Google Scholar : PubMed/NCBI

5 

Meyer KD and Jaffrey SR: Rethinking m6A readers, writers, and erasers. Annu Rev Cell Dev Biol. 33:319–342. 2017. View Article : Google Scholar : PubMed/NCBI

6 

Schumann U, Shafik A and Preiss T: METTL3 gains R/W access to the epitranscriptome. Mol Cell. 62:323–324. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, et al: Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24:177–189. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, et al: Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8:284–296. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG and Soller M: m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature. 540:301–304. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Muller S, Glaß M, Singh AK, Haase J, Bley N, Fuchs T, Lederer M, Dahl A, Huang H, Chen J, et al: IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res. 47:375–390. 2019. View Article : Google Scholar : PubMed/NCBI

11 

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG and He C: N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 7:885–887. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, et al: ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 49:18–29. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Narayan P and Rottman FM: An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. Science. 242:1159–1162. 1988. View Article : Google Scholar : PubMed/NCBI

14 

Bodi Z, Button JD, Grierson D and Fray RG: Yeast targets for mRNA methylation. Nucleic Acids Res. 38:5327–5335. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Hongay CF and Orr-Weaver TL: Drosophila inducer of MEiosis 4 (IME4) is required for Notch signaling during oogenesis. Proc Natl Acad Sci USA. 108:14855–14860. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, Su Y, Kim NS, Zhu Y, Zheng L, et al: Temporal control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell. 171:877–889 e817. 2017. View Article : Google Scholar : PubMed/NCBI

17 

McIntyre ABR, Alexander N, Grigorev K, Bezdan D, Sichtig H, Chiu CY and Mason CE: Single-molecule sequencing detection of N6-methyladenine in microbial reference materials. Nat Commun. 10:5792019. View Article : Google Scholar : PubMed/NCBI

18 

Hong T, Yuan Y, Chen Z, Xi K, Wang T, Xie Y, He Z, Su H, Zhou Y, Tan ZJ, et al: Precise Antibody-Independent m6A Identification via 4SedTTP-Involved and FTO-Assisted Strategy at Single-Nucleotide Resolution. J Am Chem Soc. 140:5886–5889. 2018. View Article : Google Scholar : PubMed/NCBI

19 

Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR: Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell. 149:1635–1646. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Shi H, Wei J and He C: Where, when, and how: Context-Dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 74:640–650. 2019. View Article : Google Scholar : PubMed/NCBI

21 

Zaccara S, Ries RJ and Jaffrey SR: Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 20:608–624. 2019. View Article : Google Scholar : PubMed/NCBI

22 

Zhao BS, Roundtree IA and He C: Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 18:31–42. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Fu Y, Dominissini D, Rechavi G and He C: Gene expression regulation mediated through reversible m6A RNA methylation. Nat Rev Genet. 15:293–306. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Warda AS, Kretschmer J, Hackert P, Lenz C, Urlaub H, Höbartner C, Sloan KE and Bohnsack MT: Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 18:2004–2014. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Doxtader KA, Wang P, Scarborough AM, Seo D, Conrad NK and Nam Y: Structural basis for regulation of METTL16, an S-adenosylmethionine homeostasis factor. Mol Cell. 71:1001–1011.e4. 2018. View Article : Google Scholar : PubMed/NCBI

26 

Guo J, Tang HW, Li J, Perrimon N and Yan D: Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex. Proc Natl Acad Sci USA. 115:3674–3679. 2018. View Article : Google Scholar : PubMed/NCBI

27 

Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M and Jaffrey SR: m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 537:369–373. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ, Smemo S, Dai Q, Bailey KA, Nobrega MA, et al: FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 4:17982013. View Article : Google Scholar : PubMed/NCBI

29 

Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H and He C: N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 161:1388–1399. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, et al: N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 505:117–120. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C and He C: YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 27:315–328. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao YJ, Ping XL, Chen YS, Wang WJ, et al: FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24:1403–1419. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Peng S, Xiao W, Ju D, Sun B, Hou N, Liu Q, Wang Y, Zhao H, Gao C, Zhang S, et al: Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med. 11:eaau71162019. View Article : Google Scholar : PubMed/NCBI

34 

Ben-Haim MS, Moshitch-Moshkovitz S and Rechavi G: FTO: Linking m6A demethylation to adipogenesis. Cell Res. 25:3–4. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Zhang C, Fu J and Zhou Y: A review in research progress concerning m6A methylation and immunoregulation. Front Immunol. 10:9222019. View Article : Google Scholar : PubMed/NCBI

36 

Ma Z, Gao X, Shuai Y, Xing X and Ji J: The m6A epitranscriptome opens a new charter in immune system logic. Epigenetics. 1–19. 2020. View Article : Google Scholar : PubMed/NCBI

37 

Shulman Z and Stern-Ginossar N: The RNA modification N(6)-methyladenosine as a novel regulator of the immune system. Nat Immunol. 21:501–512. 2020. View Article : Google Scholar : PubMed/NCBI

38 

Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, et al: Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 347:1002–1006. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Roundtree IA, Evans ME, Pan T and He C: Dynamic RNA modifications in gene expression regulation. Cell. 169:1187–1200. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Xiao S, Zeng X, Fan Y, Su Y, Ma Q, Zhu J and Yao H: Gene polymorphism association with type 2 diabetes and related gene-gene and gene-environment interactions in a uyghur population. Med Sci Monit. 22:474–487. 2016.PubMed/NCBI

41 

Kennedy EM, Bogerd HP, Kornepati AV, Kang D, Ghoshal D, Marshall JB, Poling BC, Tsai K, Gokhale NS, Horner SM and Cullen BR: Posttranscriptional m(6)A editing of HIV-1 mRNAs enhances viral gene expression. Cell host microbe. 19:675–685. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Tirumuru N, Zhao BS, Lu W, Lu Z, He C and Wu L: N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife. 5:e155282016. View Article : Google Scholar : PubMed/NCBI

43 

Gokhale NS, McIntyre ABR, McFadden MJ, Roder AE, Kennedy EM, Gandara JA, Hopcraft SE, Quicke KM, Vazquez C, Willer J, et al: N6-Methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell host microbe. 20:654–665. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Lichinchi G, Zhao BS, Wu Y, Lu Z, Qin Y, He C and Rana TM: Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe. 20:666–673. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Yu R, Li Q, Feng Z, Cai L and Xu Q: M6A Reader YTHDF2 Regulates LPS-Induced inflammatory response. Int J Mol Sci. 20:13232019. View Article : Google Scholar

46 

Nichols J and Smith A: Naive and primed pluripotent states. Cell Stem Cell. 4:487–492. 2009. View Article : Google Scholar : PubMed/NCBI

47 

Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E, Haddad B, Daneshvar K, et al: m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell stem cell. 15:707–719. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Buecker C, Srinivasan R, Wu Z, Calo E, Acampora D, Faial T, Simeone A, Tan M, Swigut T and Wysocka J: Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell stem cell. 14:838–853. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li Y, Lu Z, He C and Min J: Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat Chem Biol. 10:927–929. 2014. View Article : Google Scholar : PubMed/NCBI

50 

Kasowitz SD, Ma J, Anderson SJ, Leu NA, Xu Y, Gregory BD, Schultz RM and Wang PJ: Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genet. 14:e10074122018. View Article : Google Scholar : PubMed/NCBI

51 

Li Z, Qian P, Shao W, Shi H, He XC, Gogol M, Yu Z, Wang Y, Qi M, Zhu Y, et al: Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 28:904–917. 2018. View Article : Google Scholar : PubMed/NCBI

52 

Lobo J, Costa AL, Cantante M, Guimarães R, Lopes P, Antunes L, Braga I, Oliveira J, Pelizzola M, Henrique R and Jerónimo C: m6A RNA modification and its writer/reader VIRMA/YTHDF3 in testicular germ cell tumors: A role in seminoma phenotype maintenance. J Transl Med. 17:792019. View Article : Google Scholar : PubMed/NCBI

53 

Zhou J, Wan J, Shu XE, Mao Y, Liu XM, Yuan X, Zhang X, Hess ME, Brüning JC and Qian SB: N6-Methyladenosine guides mRNA alternative translation during integrated stress response. Mol Cell. 69:636–647.e7. 2018. View Article : Google Scholar : PubMed/NCBI

54 

Wu R, Liu Y, Yao Y, Zhao Y, Bi Z, Jiang Q, Liu Q, Cai M, Wang F, Wang Y and Wang X: FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism. Biochim Biophys Acta Mol Cell Biol Lipids. 1863:1323–1330. 2018. View Article : Google Scholar : PubMed/NCBI

55 

Liu J, Zhang X, Chen K, Cheng Y, Liu S, Xia M, Chen Y, Zhu H, Li Z and Cao X: CCR7 chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis. Immunity. 50:600–615.e15. 2019. View Article : Google Scholar : PubMed/NCBI

56 

Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, Huang X, Liu Y, Wang J, Dougherty U, et al: Anti-tumour immunity controlled through mRNA m(6)A methylation and YTHDF1 in dendritic cells. Nature. 566:270–274. 2019. View Article : Google Scholar : PubMed/NCBI

57 

Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C, et al: Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 35:677–691.e10. 2019. View Article : Google Scholar : PubMed/NCBI

58 

Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, et al: m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature. 548:338–342. 2017. View Article : Google Scholar : PubMed/NCBI

59 

Kim GW, Imam H, Khan M and Siddiqui A: N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling. J Biol Chem. 295:13123–13133. 2020. View Article : Google Scholar : PubMed/NCBI

60 

Mapperley C, van de Lagemaat LN, Lawson H, Tavosanis A, Paris J, Campos J, Wotherspoon D, Durko J, Sarapuu A, Choe J, et al: The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. J Exp Med. 218:e202008292021. View Article : Google Scholar : PubMed/NCBI

61 

Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, Hu B, Zhou J, Zhao Z, Feng M, et al: YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 18:1632019. View Article : Google Scholar : PubMed/NCBI

62 

Lin Z, Hsu PJ, Xing X, Fang J, Lu Z, Zou Q, Zhang KJ, Zhang X, Zhou Y, Zhang T, et al: Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. Cell Res. 27:1216–1230. 2017. View Article : Google Scholar : PubMed/NCBI

63 

Zhao BS and He C: ‘Gamete On’ for m6A: YTHDF2 exerts essential functions in female fertility. Mol Cell. 67:903–905. 2017. View Article : Google Scholar : PubMed/NCBI

64 

Livneh I, Moshitch-Moshkovitz S, Amariglio N, Rechavi G and Dominissini D: The m6A epitranscriptome: Transcriptome plasticity in brain development and function. Nat Rev Neurosci. 21:36–51. 2020. View Article : Google Scholar : PubMed/NCBI

65 

Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA, Poeck B, Helm M and Roignant JY: m6A modulates neuronal functions and sex determination in Drosophila. Nature. 540:242–247. 2016. View Article : Google Scholar : PubMed/NCBI

66 

Lin S, Choe J, Du P, Triboulet R and Gregory RI: The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 62:335–345. 2016. View Article : Google Scholar : PubMed/NCBI

67 

Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, Wang TT, Xu QG, Zhou WP and Sun SH: METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6 -methyladenosine-dependent primary MicroRNA processing. Hepatology. 65:529–543. 2017. View Article : Google Scholar : PubMed/NCBI

68 

Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, et al: The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 23:1369–1376. 2017. View Article : Google Scholar : PubMed/NCBI

69 

Wang Q, Geng W, Guo H, Wang Z, Xu K, Chen C and Wang S: Emerging role of RNA methyltransferase METTL3 in gastrointestinal cancer. J Hematol Oncol. 13:572020. View Article : Google Scholar : PubMed/NCBI

70 

Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z and Zhao G: METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 18:1422019. View Article : Google Scholar : PubMed/NCBI

71 

Yang DD, Chen ZH, Yu K, Lu JH, Wu QN, Wang Y, Ju HQ, Xu RH, Liu ZX and Zeng ZL: METTL3 promotes the progression of gastric cancer via targeting the MYC pathway. Front Oncol. 10:1152020. View Article : Google Scholar : PubMed/NCBI

72 

Shen C, Xuan B, Yan T, Ma Y, Xu P, Tian X, Zhang X, Cao Y, Ma D, Zhu X, et al: m6A-dependent glycolysis enhances colorectal cancer progression. Mol Cancer. 19:722020. View Article : Google Scholar : PubMed/NCBI

73 

Chen M, Wei L, Law CT, Tsang FH, Shen J, Cheng CL, Tsang LH, Ho DW, Chiu DK, Lee JM, et al: RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 67:2254–2270. 2018. View Article : Google Scholar : PubMed/NCBI

74 

Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, Li S, Tan L, Mai D, Li G, et al: Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 10:18582019. View Article : Google Scholar : PubMed/NCBI

75 

Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T, Doki Y, Mori M, Ishii H and Ogawa K: The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 52:621–629. 2018.PubMed/NCBI

76 

Liu T, Yang S, Sui J, Xu SY, Cheng YP, Shen B, Zhang Y, Zhang XM, Yin LH, Pu YP and Liang GY: Dysregulated N6-methyladenosine methylation writer METTL3 contributes to the proliferation and migration of gastric cancer. J Cell Physiol. 235:548–562. 2020. View Article : Google Scholar : PubMed/NCBI

77 

Wang P, Wang X, Zheng L and Zhuang C: Gene signatures and prognostic values of m6A regulators in hepatocellular carcinoma. Front Genet. 11:5401862020. View Article : Google Scholar : PubMed/NCBI

78 

Zhu D, Zhou J, Zhao J, Jiang G, Zhang X, Zhang Y and Dong M: ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. J Cell Physiol. 234:8899–8907. 2019. View Article : Google Scholar : PubMed/NCBI

79 

Barros-Silva D, Lobo J, Guimaraes-Teixeira C, Carneiro I, Oliveira J, Martens-Uzunova ES, Henrique R and Jerónimo C: VIRMA-Dependent N6-Methyladenosine modifications regulate the expression of long non-coding RNAs CCAT1 and CCAT2 in prostate cancer. Cancers (Basel). 12:7712020. View Article : Google Scholar

80 

Qian JY, Gao J, Sun X, Cao MD, Shi L, Xia TS, Zhou WB, Wang S, Ding Q and Wei JF: KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene. 38:6123–6141. 2019. View Article : Google Scholar : PubMed/NCBI

81 

Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, et al: FTO plays an oncogenic role in acute myeloid leukemia as a N6-Methyladenosine RNA demethylase. Cancer Cell. 31:127–141. 2017. View Article : Google Scholar : PubMed/NCBI

82 

Van Der Werf I and Jamieson C: The yin and yang of RNA methylation: An imbalance of erasers enhances sensitivity to FTO demethylase small-molecule targeting in leukemia stem cells. Cancer Cell. 35:540–541. 2019. View Article : Google Scholar : PubMed/NCBI

83 

Zhu T, Yong XLH, Xia D, Widagdo J and Anggono V: Ubiquitination regulates the proteasomal degradation and nuclear translocation of the fat mass and obesity-associated (FTO) protein. J Mol Biol. 430:363–371. 2018. View Article : Google Scholar : PubMed/NCBI

84 

Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z, Huang Y, Yang CG, et al: m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 18:2622–2634. 2017. View Article : Google Scholar : PubMed/NCBI

85 

Kwok CT, Marshall AD, Rasko JE and Wong JJ: Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia. J Hematol Oncol. 10:392017. View Article : Google Scholar : PubMed/NCBI

86 

Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al: m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 31:591–606 e6. 2017. View Article : Google Scholar : PubMed/NCBI

87 

Bai Y, Yang C, Wu R, Huang L, Song S, Li W, Yan P, Lin C, Li D and Zhang Y: YTHDF1 regulates tumorigenicity and cancer stem cell-like activity in human colorectal carcinoma. Front Oncol. 9:3322019. View Article : Google Scholar : PubMed/NCBI

88 

Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, et al: Oncogene c-Myc promotes epitranscriptome m6A reader YTHDF1 expression in colorectal cancer. Oncotarget. 9:7476–7486. 2018. View Article : Google Scholar : PubMed/NCBI

89 

Tanabe A, Tanikawa K, Tsunetomi M, Takai K, Ikeda H, Konno J, Torigoe T, Maeda H, Kutomi G, Okita K, et al: RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett. 376:34–42. 2016. View Article : Google Scholar : PubMed/NCBI

90 

Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, et al: Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 20:285–295. 2018. View Article : Google Scholar : PubMed/NCBI

91 

Zhang C, Zhang M, Ge S, Huang W, Lin X, Gao J, Gong J and Shen L: Reduced m6A modification predicts malignant phenotypes and augmented Wnt/PI3K-Akt signaling in gastric cancer. Cancer Med. 8:4766–4781. 2019. View Article : Google Scholar : PubMed/NCBI

92 

Korshunov A, Sahm F, Zheludkova O, Golanov A, Stichel D, Schrimpf D, Ryzhova M, Potapov A, Habel A, Meyer J, et al: DNA methylation profiling is a method of choice for molecular verification of pediatric WNT-activated medulloblastomas. Neuro Oncol. 21:214–221. 2019. View Article : Google Scholar : PubMed/NCBI

93 

Zhang L, Wan Y, Zhang Z, Jiang Y, Lang J, Cheng W and Zhu L: FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway. RNA Biol. Nov 5–2020.(Epub ahead of print). doi: 10.1080/15476286.2020.1841458. View Article : Google Scholar

94 

Liu L, Wang J, Sun G, Wu Q, Ma J, Zhang X, Huang N, Bian Z, Gu S, Xu M, et al: m6A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma. Mol Cancer. 18:1882019. View Article : Google Scholar : PubMed/NCBI

95 

Le PN, McDermott JD and Jimeno A: Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 146:1–11. 2015. View Article : Google Scholar : PubMed/NCBI

96 

Li Z, Chen Y, An T, Liu P, Zhu J, Yang H, Zhang W, Dong T, Jiang J, Zhang Y, et al: Nuciferine inhibits the progression of glioblastoma by suppressing the SOX2-AKT/STAT3-Slug signaling pathway. J Exp Clin Cancer Res. 38:1392019. View Article : Google Scholar : PubMed/NCBI

97 

Li M, Bu X, Cai B, Liang P, Li K, Qu X and Shen L: Biological role of metabolic reprogramming of cancer cells during epithelialmesenchymal transition (Review). Oncol Rep. 41:727–741. 2019.PubMed/NCBI

98 

Chen J, Sun Y, Xu X, Wang D, He J, Zhou H, Lu Y, Zeng J, Du F, Gong A and Xu M: YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle. 16:2259–2271. 2017. View Article : Google Scholar : PubMed/NCBI

99 

Chen WW, Qi JW, Hang Y, Wu JX, Zhou XX, Chen JZ, Wang J and Wang HH: Simvastatin is beneficial to lung cancer progression by inducing METTL3-induced m6A modification on EZH2 mRNA. Eur Rev Med Pharmacol Sci. 24:4263–4270. 2020.PubMed/NCBI

100 

Aoki M and Fujishita T: Oncogenic roles of the PI3K/AKT/mTOR axis. Curr Top Microbiol Immunol. 407:153–189. 2017.PubMed/NCBI

101 

Li X, Tang J, Huang W, Wang F, Li P, Qin C, Qin Z, Zou Q, Wei J, Hua L, et al: The M6A methyltransferase METTL3: Acting as a tumor suppressor in renal cell carcinoma. Oncotarget. 8:96103–96116. 2017. View Article : Google Scholar : PubMed/NCBI

102 

Zhao Q, Zhao Y, Hu W, Zhang Y, Wu X, Lu J, Li M, Li W, Wu W, Wang J, et al: m6A RNA modification modulates PI3K/Akt/mTOR signal pathway in gastrointestinal cancer. Theranostics. 10:9528–9543. 2020. View Article : Google Scholar : PubMed/NCBI

103 

Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, Li C, Sun L, Qin J, Xu T, et al: METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 19:1062020. View Article : Google Scholar : PubMed/NCBI

104 

Bi X, Lv X, Liu D, Guo H, Yao G, Wang L, Liang X and Yang Y: METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway. Cancer Gene Ther. Sep 16–2020.(Epub ahead of print). doi: 10.1038/s41417-020-00222-3. View Article : Google Scholar

105 

Liu J, Eckert MA, Harada BT, Liu SM, Lu Z, Yu K, Tienda SM, Chryplewicz A, Zhu AC, Yang Y, et al: m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 20:1074–1083. 2018. View Article : Google Scholar : PubMed/NCBI

106 

Salaroglio IC, Mungo E, Gazzano E, Kopecka J and Riganti C: ERK is a pivotal player of chemo-immune-resistance in cancer. Int J Mol Sci. 20:25052019. View Article : Google Scholar

107 

Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, Ma H and Kang T: YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 442:252–261. 2019. View Article : Google Scholar : PubMed/NCBI

108 

Sun HL, Zhu AC, Gao Y, Terajima H, Fei Q, Liu S, Zhang L, Zhang Z, Harada BT, He YY, et al: Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A methylation. Mol Cell. 80:633–647.e7. 2020. View Article : Google Scholar : PubMed/NCBI

109 

Xie JW, Huang XB, Chen QY, Ma YB, Zhao YJ, Liu LC, Wang JB, Lin JX, Lu J, Cao LL, et al: m6A modification-mediated BATF2 acts as a tumor suppressor in gastric cancer through inhibition of ERK signaling. Mol Cancer. 19:1142020. View Article : Google Scholar : PubMed/NCBI

110 

Ghazi T, Nagiah S and Chuturgoon AA: Fusaric acid decreases p53 expression by altering promoter methylation and m6A RNA methylation in human hepatocellular carcinoma (HepG2) cells. Epigenetics. 1–13. 2020.(Epub ahead of print).

111 

Ding H, Zhang X, Su Y, Jia C and Dai C: GNAS promotes inflammation-related hepatocellular carcinoma progression by promoting STAT3 activation. Cell Mol Biol Lett. 25:82020. View Article : Google Scholar : PubMed/NCBI

112 

Zhang Z, Zhou D, Lai Y, Liu Y, Tao X, Wang Q, Zhao G, Gu H, Liao H, Zhu Y, et al: Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett. 319:89–97. 2012. View Article : Google Scholar : PubMed/NCBI

113 

Zhu Y, Shen J, Gao L and Feng Y: Estrogen promotes fat mass and obesity-associated protein nuclear localization and enhances endometrial cancer cell proliferation via the mTOR signaling pathway. Oncol Rep. 35:2391–2397. 2016. View Article : Google Scholar : PubMed/NCBI

114 

Wang Q, Chen C, Ding Q, Zhao Y, Wang Z, Chen J, Jiang Z, Zhang Y, Xu G, Zhang J, et al: METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 69:1193–1205. 2020. View Article : Google Scholar : PubMed/NCBI

115 

Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, Chen ZH, Zeng ZL, Wang F, Zheng J, et al: METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 18:1122019. View Article : Google Scholar : PubMed/NCBI

116 

Li Y, Zheng D, Wang F, Xu Y, Yu H and Zhang H: Expression of demethylase genes, FTO and ALKBH1, is associated with prognosis of gastric cancer. Dig Dis Sci. 64:1503–1513. 2019. View Article : Google Scholar : PubMed/NCBI

117 

Wang S, Chai P and Jia R and Jia R: Novel insights on m6A RNA methylation in tumorigenesis: A double-edged sword. Mol Cancer. 17:1012018. View Article : Google Scholar : PubMed/NCBI

118 

Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M, Liang Y, Zhu F, Zhang Y, Zhang X, et al: The m(6)A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-kappaB/MYC signaling network. Oncogene. 38:3667–3680. 2019. View Article : Google Scholar : PubMed/NCBI

119 

Li F, Yi Y, Miao Y, Long W, Long T, Chen S, Cheng W, Zou C, Zheng Y, Wu X, et al: N6-Methyladenosine modulates nonsense-mediated mRNA decay in human glioblastoma. Cancer Res. 79:5785–5798. 2019. View Article : Google Scholar : PubMed/NCBI

120 

Wang K, Jiang L, Zhang Y and Chen C: Progression of thyroid carcinoma is promoted by the m6A methyltransferase METTL3 through regulating m6A methylation on TCF1. Onco Targets Ther. 13:1605–1612. 2020. View Article : Google Scholar : PubMed/NCBI

121 

Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C, et al: METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell. 22:191–205.e9. 2018. View Article : Google Scholar : PubMed/NCBI

122 

Bansal H, Yihua Q, Iyer SP, Ganapathy S, Proia DA, Penalva LO, Uren PJ, Suresh U, Carew JS, Karnad AB, et al: WTAP is a novel oncogenic protein in acute myeloid leukemia. Leukemia. 28:1171–1174. 2014. View Article : Google Scholar : PubMed/NCBI

123 

Chen Y, Peng C, Chen J, Chen D, Yang B, He B, Hu W, Zhang Y, Liu H, Dai L, et al: WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1. Mol Cancer. 18:1272019. View Article : Google Scholar : PubMed/NCBI

124 

Cheng X, Li M, Rao X, Zhang W, Li X, Wang L and Huang G: KIAA1429 regulates the migration and invasion of hepatocellular carcinoma by altering m6A modification of ID2 mRNA. Onco Targets Ther. 12:3421–3428. 2019. View Article : Google Scholar : PubMed/NCBI

125 

Xu D, Shao W, Jiang Y, Wang X, Liu Y and Liu X: FTO expression is associated with the occurrence of gastric cancer and prognosis. Oncol Rep. 38:2285–2292. 2017. View Article : Google Scholar : PubMed/NCBI

126 

Li J, Han Y, Zhang H, Qian Z, Jia W, Gao Y, Zheng H and Li B: The m6A demethylase FTO promotes the growth of lung cancer cells by regulating the m6A level of USP7 mRNA. Biochem Biophys Res Commun. 512:479–485. 2019. View Article : Google Scholar : PubMed/NCBI

127 

Li J, Zhu L, Shi Y, Liu J, Lin L and Chen X: m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res. 11:6084–6092. 2019.PubMed/NCBI

128 

Chao Y, Shang J and Ji W: ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia. Biochem Biophys Res Commun. 521:499–506. 2020. View Article : Google Scholar : PubMed/NCBI

129 

Lin X, Chai G, Wu Y, Li J, Chen F, Liu J, Luo G, Tauler J, Du J, Lin S, et al: RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 10:20652019. View Article : Google Scholar : PubMed/NCBI

130 

Li J, Xie H, Ying Y, Chen H, Yan H, He L, Xu M, Xu X, Liang Z, Liu B, et al: YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 19:1522020. View Article : Google Scholar : PubMed/NCBI

131 

Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, Qiu Z, Kidwell RL, Kim LJ, Xie Q, et al: The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. Cancer Discov. 11:480–499. 2021. View Article : Google Scholar : PubMed/NCBI

132 

Chang G, Shi L, Ye Y, Shi H, Zeng L, Tiwary S, Huse JT, Huo L, Ma L, Ma Y, et al: YTHDF3 induces the translation of m6A-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell. 38:857–871 e7. 2020. View Article : Google Scholar : PubMed/NCBI

133 

Ma L, Chen T, Zhang X, Miao Y, Tian X, Yu K, Xu X, Niu Y, Guo S, Zhang C, et al: The m6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 38:1018012021. View Article : Google Scholar : PubMed/NCBI

134 

Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, Li J, An P, Lu L, Luo N, et al: m6A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 18:872019. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April-2021
Volume 45 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Liu F and Liu F: Effects of m6A modifications on signaling pathways in human cancer (Review). Oncol Rep 45: 36, 2021
APA
Liu, F., & Liu, F. (2021). Effects of m6A modifications on signaling pathways in human cancer (Review). Oncology Reports, 45, 36. https://doi.org/10.3892/or.2021.7987
MLA
Liu, F., Su, X."Effects of m6A modifications on signaling pathways in human cancer (Review)". Oncology Reports 45.4 (2021): 36.
Chicago
Liu, F., Su, X."Effects of m6A modifications on signaling pathways in human cancer (Review)". Oncology Reports 45, no. 4 (2021): 36. https://doi.org/10.3892/or.2021.7987