IJMMInternational Journal of Molecular Medicine1107-37561791-244XD.A. Spandidos10.3892/ijmm.2025.5605ijmm-56-04-05605Reviewm6A modification of non-coding RNA: Mechanisms, functions and potential values in human diseases (Review)YiQian1*LiaoYi2*SunWei3*LiJiachen3YangDahang3ShangHongxi3SunWeichao3
Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646099, P.R. China
Department of Technical Support, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Jiangsu 530021, P.R. China
Department of Orthopedics, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. ChinaCorrespondence to: Professor Hongxi Shang or Professor Weichao Sun, Department of Orthopedics, Shenzhen Second People's Hospital, 3002 Sungang West Road, Futian, Shenzhen, Guangdong 518035, P.R. China, E-mail: 992369157@qq.com, E-mail: weichaosunshine@163.com
N6-methyladenosine (m6A) RNA modification represents a pivotal and novel post-transcriptional modification in eukaryotic RNAs. Initially identified in messenger RNAs (mRNAs), m6A modification on these transcripts regulates a spectrum of essential cellular processes, including mRNA splicing, subcellular localization, stability and translation. Recent studies have highlighted the involvement of m6A methylation in both biological and pathological processes, particularly in cancer. Non-coding RNAs (ncRNAs), a diverse class of RNA molecules that do not encode proteins, encompass microRNAs, long ncRNAs and circular RNAs. Notably, m6A has been recognized as a reversible epigenetic modification within ncRNAs, a discovery that has garnered considerable attention. This modification not only influences the stability of ncRNAs but also endows them with the novel capacity for peptide translation. The differential and specific expression pattern in diseases give these m6A-modified ncRNAs potential as biomarkers for molecular diagnostics and targeted therapy, and using ncRNA-encoded peptides as a target for immunotherapy has also been attempted. This review synthesizes the current understanding of m6A modifications in ncRNAs, explores the effects of m6A on ncRNA function and presents the latest insights into the role of ncRNA m6A modifications in disease progression.
Key wordsm6A modificationlncRNAscircRNAspeptidesShenzhen Medical Research FundA2403030Scientific Research Foundation of Southwest Medical University2021ZKMS009Shenzhen Science and Technology ProjectsKCXFZ20230731093059012JSGG20220831110400001This research was supported by the Shenzhen Medical Research Fund (grant no. A2403030); the Scientific Research Foundation of Southwest Medical University (grant no. 2021ZKMS009); and Shenzhen Science and Technology Projects (grant nos. KCXFZ20230731093059012 and JSGG20220831110400001).Introduction
RNA methylation is a key epigenetic modification that regulates gene transcription without altering the underlying gene sequence. Key types of RNA methylation include N6-methyladenosine (m6A), 5-methylcytosine, m1A, N7-methylguanosine and 3-methylcytidine (1,2). Among these, m6A is the most prevalent and extensively studied RNA modification. As the name suggests, m6A occurs at the N6 position of adenosine, with two predominant motifs-RRACH and DRACH-where H represents U, A or C; R denotes A or G; and D refers to U, A or G (3). This modification plays a pivotal role in various aspects of RNA metabolism, including splicing, transport, localization, translation and degradation (4,5). Numerous studies have demonstrated that m6A is critical for physiological processes, such as embryonic development (6), and it has also been implicated in various pathological processes, including cancer (7,8).
In eukaryotic cells, non-coding RNAs (ncRNAs) are a class of endogenous RNA molecules that do not encode proteins (9). These ncRNAs can be categorized into several types, including transfer RNAs, microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) (10,11). Although ncRNAs do not directly translate into proteins, they perform vital biological functions at the RNA level. They can interact with DNA, mRNA and proteins, playing specialized roles in the regulation of gene expression, mRNA stability and protein function (12-14). Dysregulation of ncRNAs has been strongly linked to the progression of various diseases and malignancies.
Recent studies have expanded the understanding of m6A modifications in ncRNAs (15,16). m6A methylation regulates the transcription, structural stability, localization and translation of ncRNAs. Importantly, the abnormal changes induced by m6A modification enable ncRNAs to participate in diverse biological and pathological processes, including cancer. For instance, peptides derived from m6A-modified ncRNAs have been reported to exhibit both oncogenic and tumor-suppressive functions (17,18). Therefore, the roles of m6A modification in ncRNAs and their underlying mechanisms warrant further investigation, with the potential to uncover novel biomarkers for disease diagnosis, prognostic indicators and therapeutic strategies.
The present review synthesizes recent findings on m6A modifications in ncRNAs, focusing on their impact on the stability, localization and translation of ncRNAs. Additionally, it discusses the involvement of m6A-modified ncRNAs in disease progression and tumorigenesis, providing new insights into the role of m6A modification in ncRNA biology and facilitating further research in this area.
m6A modification
After transcription, RNA nucleosides, including adenosine, guanosine, cytidine and uridine, can undergo additional chemical modifications, adding complexity to their function. One such modification is m6A, where a methyl group is added to the N6 position of adenosine. Since its discovery in 1974, m6A has been recognized as a prevalent and abundant modification in mRNAs, and it remains one of the most extensively studied RNA modifications to date (19,20). Extensive research has demonstrated that m6A modifications play a pivotal role in various physiological processes and are implicated in numerous diseases, including obesity, diabetes, gastrointestinal disorders, Alzheimer's disease (AD) and cancers (21,22).
m6A methylation is a dynamic and reversible post-transcriptional modification that sets it apart from other forms of epigenetic regulation (Fig. 1). This reversible process is mediated by enzymes and proteins involved in the m6A modification, including 'writers' and 'erasers' (4). The m6A writers, or methyltransferases, include methyltransferase-like 3 (METTL3), METTL5, METTL14, METTL16, Wilms' tumor 1-associated protein (WTAP), RNA binding motif protein 15/15B (RBM15/15B), zinc finger CCCH-type containing 13 and KIAA1429 (also known as vir-like m6A methyltransferase associated protein). These enzymes form a methyltransferase complex that catalyzes the addition of m6A to RNA molecules (23-25). Conversely, m6A erasers, or demethylases, such as fat mass and obesity-associated protein (FTO) and α-ketoglutarate-dependent dioxygenase alk B homolog 5 (ALKBH5), are responsible for removing m6A modifications from target RNA molecules (2,26,27). The m6A readers are the key enzymes, as they recognize the m6A sites on RNA molecules and mediate the influence of m6A on the fate of mRNA. The YTH domain family (YTHDF) represents the most common group of m6A readers. YTHDF1 enhances mRNA translation, while YTHDF2 promotes mRNA degradation, and YTHDF3 works in concert with YTHDF1 and YTHDF2 to regulate mRNA metabolism. YTHDC1 and YTHDC2, other key m6A readers, are involved in RNA splicing, cytoplasmic-nuclear shuttling and stability (28-30). The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family, comprising IGF2BP1, IGF2BP2 and IGF2BP3, protects m6A-modified mRNAs from degradation within P-bodies and stress granules (31-33). Other m6A readers, such as heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and serine and arginine rich splicing factor 9, have been shown to regulate mRNA stability, localization and translation (34,35). While the majority of studies on m6A focus on mRNA molecules, emerging evidence indicates that ncRNAs can also undergo m6A modification, which regulates their stability, localization and translation.
The m6A modification can be detected along with the development of detection technologies. Single-molecule epitranscriptomic analysis and single-molecule sequencing could detect and reveal functional roles of site-specific m6As (36,37). However, high-throughput sequencing or in vitro assays are not reflected in the dynamic changes of m6A modification, and current in situ imaging techniques for site-specific m6A are constrained. Recently, Song et al (38) presented a method, termed proximity hybridization followed by primer exchange amplification, which could image m6A methylation sites concurrently in multiple cell types, revealing cell-to-cell variability in expression levels. Furthermore, Zhang et al (39) introduced the TadA8.20-assisted N6-methyladenosine RNA imaging at single-base resolution method for precise visualization and quantification of both A and m6A forms at specific RNA sites within single cells. With the development of detection technology, detecting dynamic changes in m6A modification can provide a more accurate basis for molecular diagnosis and targeted therapy of diseases.
NcRNAs
NcRNAs are a diverse group of endogenous RNA molecules that typically do not encode proteins (10). These ncRNAs can be categorized into several classes: LncRNAs, which are longer than 200 nucleotides (nt); small ncRNAs, including miRNAs and small nuclear RNAs, which are shorter than 200 nt; circRNAs; small interfering RNAs; piwi-interacting RNAs; and ribosomal RNAs.
MiRNAs are a well-conserved class of endogenous ncRNAs ~22 nucleotides in length (40). They interact with mRNAs, regulating their degradation, translational repression or direct cleavage in a post-transcriptional manner (41,42). >2,600 miRNAs have been identified in the human genome and are known to regulate the expression of 30-50% of functional genes. Small nuclear RNAs, averaging 150 nucleotides, are primarily located in the nucleus and are core components of small nuclear ribonucleoproteins, which are essential for RNA splicing (43,44).
Like typical RNA molecules, lncRNAs possess a 5′-methyl-cytosine cap and a 3′-poly(A) tail (45). In the canonical pathway, lncRNAs are transcribed by RNA polymerase II. They may be cleaved by ribonuclease P or recognized by small nucleolar RNA-protein complexes and other enzymes to produce mature 3′ ends, capping structures or circular forms in non-canonical pathways (46,47). Based on their genomic origins, lncRNAs can be classified into five categories: Sense lncRNAs, antisense lncRNAs, bidirectional lncRNAs, intronic lncRNAs and intergenic lncRNAs (48). Initially, lncRNAs were thought to be non-coding and to primarily act as RNA sponges or sponges for RNA-binding proteins (RBPs) (49,50).
CircRNAs are a distinct class of ncRNA characterized by a covalently closed loop structure (51). They are generated through back-splicing, where a downstream splice donor site is joined with an upstream splice acceptor site (52). CircRNAs can be further classified into three major groups based on their genomic origins: Circular intronic RNAs, exon-intron circRNAs and exonic circRNAs (53). CircRNAs have been shown to regulate transcription, RNA stability, localization and protein function by binding to DNA, RNA molecules or proteins (54,55).
The dysregulation of miRNAs, lncRNAs and circRNAs has been implicated in various biological processes, primarily through their ability to sponge RNA molecules or proteins (56,57). Recently, it has been discovered that lncRNAs and circRNAs containing internal ribosome entry sites or m6A modification sites can be translated into micro-peptides (58,59). These novel findings provide critical insights for further research.
m6A modification of ncRNAsm6A modification of miRNAs
In the case of miRNAs, m6A modification has been shown to impact their biogenesis and subsequently alter the functionality of mature miRNAs. Garbo et al (16) demonstrated that m6A modification on specific miRNAs affects argonaute 2 (AGO2)/miRNA and RBP/miRNA interactions, impairing their ability to regulate target mRNAs and influencing extracellular vesicle (EV) loading. Alarcón et al (60) highlighted m6A methylation as a critical mechanism in miRNA biogenesis. METTL3-mediated m6A methylation promotes the maturation of pri-miR-BART3-3p by interacting with DGCR8, thereby facilitating Natural killer/T cell lymphoma progression (25). Similarly, METTL14 modulates pri-miR-100 processing to mature miR-100-3p in an m6A-dependent manner through DGCR8 microprocessor complex subunit (DGCR8) during ultraviolet B-induced human dermal fibroblast photoaging (61). In addition, ALKBH5 demethylates pri-miR-194-2, suppressing miR-194-2 biogenesis via an m6A/DGCR8-dependent pathway (62), while FTO inhibits DGCR8 binding to pri-miR-138-5p through m6A modification, thereby limiting miR-138-5p processing (63). Furthermore, YTHDF2 recognizes m6A sites in pre-miR-126 and recruits AGO2 to enhance the maturation of pre-miR-126 into mature miR-126 (51). YTHDC1 promotes the biogenesis of mature miR-30d through m6A-mediated regulation of mRNA stability (64).
m6A modification of lncRNAs
Numerous studies have reported the m6A modification of lncRNAs. Bian et al (65) found that METTL3 mediates the m6A modification of lncRNA ABHD11-antisense 1 (AS1), which inhibits ferroptosis and promotes colorectal cancer (CRC) progression. Likewise, Zhao et al (66) identified METTL3 as a key factor in enhancing the m6A modification of homeobox (HOX)A10-AS, thereby increasing its RNA stability. METTL14-mediated m6A modification stabilizes lncRNA THRIL (TNF and HNRNPL related immunoregulatory lncRNA), accelerating lipopolysaccharide (LPS)-induced acute injury in alveolar epithelial cells (67). Furthermore, WTAP-mediated m6A modification enhances the stability of lnc-OXAR, which contributes to oxaliplatin resistance in non-alcoholic steatohepatitis-related hepatocellular carcinoma (HCC) (68). Additionally, FTO has been shown to suppress the m6A modification of lncRNA small nucleolar RNA host gene 1 (SNHG14), attenuating LPS-induced acute kidney injury by inhibiting autophagy (69). ALKBH5 decreases m6A-modified sites on DNA damage inducible transcript 4 (DDIT4)-AS1, inhibiting the recruitment of ELAV-like RNA binding protein 1 and stabilizing DDIT4-AS1 (70).
m6A modification of circRNAs
CircRNAs are also subject to m6A modification. Chen et al (71) demonstrated that METTL3 promotes the m6A modification of circ-CTTN, thereby enhancing osteogenic differentiation of human umbilical cord mesenchymal stem cells (MSCs). Fan et al (72) uncovered that METTL14 mediates m6A modification of circORC5, which suppresses gastric cancer (GC) progression. Additionally, WTAP-mediated m6A modification of circ_0056856 promotes proliferation, migration and invasion of interleukin-22-stimulated human keratinocytes (73). ALKBH5 has also been reported to regulate the demethylation of circCPSF6, influencing its recognition and stabilization by YTHDF2 (74). The ALKBH5/insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) axis mediates the m6A modification of circXPO1, which accelerates CRC progression (75). Furthermore, Wu et al (76) found that FTO binds to circFAM192A at specific sites, removing the m6A modification and protecting it from degradation.
Function of m6A modification on ncRNAs
For mRNAs, the roles of m6A modification are well-established, encompassing various aspects of RNA metabolism, including splicing, transportation, translation and degradation. For ncRNAs, m6A modification plays a critical role in regulating their biogenesis, stability, localization and even translation (Fig. 2).
Regulating the biogenesis and expression of ncRNAs
As widely recognized, m6A modification impacts the biogenesis and functionality of mature miRNAs. In addition, m6A modulates RNA splicing, which is essential for the biogenesis of circRNAs. For instance, circDDIT4 is generated by back-splicing at the 3′-UTR using a 5′ splice acceptor site in exon 2 of linear DDIT4 mRNA. The WTAP/METTL3/METTL14 methyltransferase complex mediates m6A modification in both the circDDIT4-5′ flanking and circDDIT4-3′-UTR regions, promoting circDDIT4 circularization (77). METTL3/YTHDC1-mediated m6A modification regulates the biogenesis of circRBM33, generated from exon 3 to exon 5 of RBM33 mRNA (78). Similarly, METTL3/YTHDC1-mediated m6A modification and back-splicing events contribute to the biogenesis of circCDYL (79). METTL3 increases m6A modification of circARL3, with YTHDC1 binding to modified sites and facilitating reverse splicing and circularization (80). METTL3 also mediates the m6A modification of circIGF2BP3, promoting its circularization in an m6A-dependent manner through YTHDC1 (81). The m6A reader YTHDC1, along with the RNA helicase DEAD-box helicase 5 (DDX5), regulates the production of circRNAs enriched in rhabdomyosarcoma (82). Furthermore, the upregulation of lncRNA CHASERR in response to m6A modification is facilitated by METTL3/YTHDF1-mediated RNA transcripts (83). Silencing METTL14 suppresses DHRS4-AS1 expression by reducing the m6A modification of DHRS4-AS1 transcripts (84). Additionally, Chen et al (85) reported that suppressing METTL3 inhibits the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). ALKBH5 promotes the upregulation of lncRMRP expression through demethylation (86) and enhances the expression of the lncRNA DIO3OS via m6A modification (87).
Regulating the stability of ncRNAs
m6A modification has been demonstrated to play a pivotal role in regulating the stability of lncRNAs and circRNAs. For instance, m6A modification is significantly enriched in lncRNA RMRP, enhancing its RNA stability (88). In addition, METTL14-induced m6A modification stabilizes lncRNA-PLCB1, thereby inhibiting GC progression through the destabilization of DDX21 (89). Xie et al (90) demonstrated that IGF2BP3 binds to m6A-modified sites on lncRNA OIP5-AS1, stabilizing its expression. Similarly, Luo et al (91) highlighted the critical role of m6A modification in maintaining the stability of lncRNA FAM83H-AS1, facilitated by METTL3 and the readers IGF2BP2/IGF2BP3. Furthermore, ALKBH5 demethylates lncRNA-CARMN, reducing its m6A modification, while YTHDF2/YTHDF3 recognizes and degrades m6A-modified lncRNA-CARMN (92). The demethylation of lncRNA SNHG15 by ALKBH5 enhances its stability (93). The abundance of m6A modification sites on lncRNA TP53TG1 is countered by ALKBH5, which reduces its stability and downregulates its expression (94). hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1 in an m6A-dependent manner (95). Yi et al (96) identified the m6A modification of circPSMA7, noting that IGF2BP3 recognizes these sites and stabilizes circPSMA7, thereby enhancing its expression. Furthermore, the upregulation of circ_104797 in cisplatin-resistant bladder cancer is attributed to increased stability driven by elevated m6A levels in its sequence (97). Similarly, the increased stability of circPLPP4 in cisplatin-resistant ovarian cancer is mediated by heightened m6A modification (98). The elevated level of circ_0000337 in bortezomib-resistant multiple myeloma cells results from augmented m6A levels, leading to enhanced RNA stability (99). METTL3-mediated m6A methylation of circSLCO1B3 stabilizes its expression, with m6A-modified circSLCO1B3 promoting intrahepatic cholangiocarcinoma progression via regulation of HOXC8 and programmed cell death ligand 1 (100). Finally, FTO acts as an eraser, increasing the stability and expression of circBRCA1 by demethylating its m6A modification, thereby alleviating oxidative stress-induced granulosa cell damage (101).
Table I summarizes additional studies on the role of m6A modification in regulating ncRNA stability and the functional implications of these ncRNAs in various diseases (102-142).
Regulating the localization of ncRNAs
m6A modification also plays a pivotal role in the localization of ncRNAs, influencing their shuttling between the cytoplasm and nucleus. The m6A modification of circNSUN2 facilitates its export to the cytoplasm, enhancing the stability of HMGA2 mRNA and promoting CRC metastasis (143). Similarly, circPAK2 undergoes m6A modification, which is recognized by YTHDC1, enabling its nuclear export to the cytoplasm and subsequently promoting lymph node metastasis in GC (144). In parallel, YTHDC1 directly binds to the m6A sites on various circRNAs, including hsa_ circ_0102678 (145), circFNDC3B (146), circPOLR2B (147), circRNA3634 (148) and circHPS5 (149), promoting their export to the cytoplasm. Furthermore, METTL3 mediates the m6A modification of LINC00294, with YTHDC1 recognizing the m6A sites and promoting its cytoplasmic localization (150). Similarly, YTHDF1 interacts with the m6A site of lncRNA FOXD1-AS1, facilitated by METTL3, thereby promoting its cytoplasmic localization (151). In addition, hnRNPC mediates the cytoplasmic export of m6A-modified circMARK2 (152). METTL3-induced m6A modification also facilitates the export of circTEAD1 to the cytoplasm (153).
Beyond localization, m6A modification of ncRNAs also regulates nuclear retention or translocation, impacting gene transcription. For instance, circPPAP2B harbors m6A sites that recruit hnRNPC in an m6A-dependent manner, facilitating the nuclear translocation of hnRNPC, which subsequently regulates alternative splicing of pre-mRNA (154). The m6A modification of circCCDC134 by ALKBH5/YTHDF2 recruits p65 in the nucleus, ultimately stimulating HIF1A transcription and facilitating cancer cell growth and metastasis (137). In addition, circMMP9 is stabilized by IGF2BP2 in an m6A-dependent manner, with circMMP9 recruiting ETS1 to promote tripartite motif containing 59 (TRIM59) transcription (155). Furthermore, DNA damage has been shown to increase m6A levels on NEAT1, promoting structural alterations and the accumulation of hypermethylated NEAT1 at promoter-associated double-strand breaks (156). METTL3-induced m6A modification upregulates POU6F2-AS1, tethering Y-box binding protein 1 to the fatty acid synthase promoter and activating transcription (157). Allele-specific m6Ad methylation affects YTHDC1-mediated protein binding affinity, with the LOC339803-YTHDC1 interaction determining chromatin localization of LOC339803, inducing the expression of NF-κB-mediated proinflammatory cytokines (158). Additionally, Vaid et al (159) reported that m6A-mediated recruitment of hnRNPA2B1 to lncRNA-TERRA is essential for R-loop formation and telomere localization.
m6A modification plays a pivotal role in sorting ncRNAs into exosomes through interactions with m6A-binding proteins. For instance, the m6A reader hnRNPA2B1 contributes to the progression of multiple myeloma osteolytic bone disease by modulating the expression and exosomal transport of miRNAs to recipient monocytes or MSCs (160). Wei et al (79) demonstrated that m6A modification of circCDYL promotes its active sorting into exosomes via hnRNPA2/B1. Similarly, the m6A modification of circCCAR1, mediated by WTAP, facilitates its secretion by HCC cells into exosomes in a hnRNPA2B1-dependent manner (161). Exosomal encapsulation of circHIF1α is also governed by hnRNPA2B1 (162). Furthermore, multiple myeloma cells enhance the packaging of lncRNA into adipocyte-derived exosomes through METTL7A-mediated m6A methylation (163). Additionally, m6A modification drives the sorting of LINC00657 into exosomes, promoting breast cancer progression by inducing macrophage M2 polarization (164). He et al (165) reported that m6A modification, recognized by IGF2BP2, stabilizes TRPM2-AS and enhances its exosomal sorting. Other m6A readers, such as RNA binding motif protein X-linked (RBMX), may also play significant roles in exosome cargo loading (166), with RBMX being a newly identified m6A reader involved in this process (167). Table II summarizes other studies on the role of m6A modification in regulating ncRNA localization (168-179).
m6A-dependent peptides translation of ncRNAs
Traditionally, ncRNAs were considered non-coding and incapable of serving as a template for producing proteins or peptides. However, recent research has challenged this notion, revealing that ncRNAs can indeed be translated into micro-peptides in an m6A modification-dependent manner. It has been reported that circSLC9A6 encodes a novel peptide, SLC9A6-126 amino-acid (aa), through m6A modification, involving the m6A reader YTHDF2 (180). Similarly, circYAP encodes a truncated protein, YAP-220aa, through m6A modification, facilitated by YTHDF3 and the eIF4G2 translation initiation complex (181). YTHDF1 and YTHDF3 bind to m6A sites on circYthdc2, promoting its translation into the Ythdc2-170aa peptide (182). Li et al (183) discovered that circFBXW7 can be translated into the short polypeptide circFBXW7-185aa, involving the m6A reader YTHDF3. In a related study, circ-MIB2 harbors m6A sites that recruit YTHDF1 and YTHDF3, facilitating its translation into the MIB2-134aa (184). Tang et al (185) demonstrated that several male germ cell circRNAs contain large open reading frames with m6A-modified start codons in their junctions, a characteristic recently associated with protein-coding potential. Additionally, circFNDC3B, modified by m6A, is translocated to the cytoplasm, and Pan et al (186) found that circFNDC3B encodes a novel protein, circF-NDC3B-218aa. METTL3-mediated m6A-modified circGLIS3 contributes to β-cell dysfunction by encoding the protein Glis3-348aa (187). The stability of circ-ZNF609 is regulated by m6A methylation and circ-ZNF609 plays a pivotal role in fibroblast activation through peptide encoding (188).
The m6A modification also plays a critical role in the translation of lncRNAs. Wu et al (189) identified a novel micro-peptide, YY1BM, encoded by the Y-linked LINC00278, where reduced m6A modification led to decreased translation. Additionally, the translation of AFAP1-AS1 translated mitochondrial-localized peptide (ATMLP) peptides from lncRNA AFAP1-AS1 was found to be regulated by m6A methylation at the adenine locus 1,313 of AFAP1-AS1 (190). Furthermore, METTL3 catalyzed the installation of m6A modification, enhancing the stability of the METTL4-2 transcript and thereby increasing its expression. In parallel, YTHDF1 recognized these m6A sites, facilitating the translation of METTL4-2 (191). Moreover, m6A modification regulates the expression of various lncRNAs, some of which have been reported to encode micro-peptides. For instance, YTHDC1 was found to upregulate the expression of HOXB-AS3 through m6A modification of its precursor RNA (192), and a micro-peptide encoded by HOXB-AS3 was reported to promote the proliferation and viability of oral squamous cell carcinoma cells (193). Another novel peptide, HOXB-AS3-32aa encoded by lncRNA HOXB-AS3, was found to promote cigarette smoke-induced inflammation and apoptosis (194). Additionally, the micro-peptide ATP synthase-associated peptide encoded by LINC00467 has been shown to promote CRC progression (195), although Zhang et al (196) recently reported the negative impact of m6A methylation on LINC00467 translation. The development of m6A sequencing technologies has led to the identification of numerous lncRNAs undergoing m6A modification, suggesting the potential for a significant number of lncRNA-encoded proteins. Table III summarizes other studies on m6A-related circRNA and lncRNA translation (197-211).
m6A modification of ncRNAs in other diseasesm6A modification of ncRNAs in cardiovascular disorders
Atherosclerosis (AS), myocardial infarction injury, myocardial ischemia-reperfusion injury and cardiac hypertrophy are the most common cardiovascular diseases. It has been reported that m6A modification of ncRNAs participates in the pathological processes of cardiovascular diseases (Fig. 3). METTL14-mediated m6A modification upregulated circARHGAP12 and aspartate beta-hydroxylase to aggravate overload-induced lipid peroxidative damage and facilitate AS progression (212). Shen et al (213) reported that hypoxia triggers cardiomyocyte apoptosis via regulating the m6A methylation-mediated lncMIAT/miR-708-5p/p53 axis. ALKBH5 decreased the N6-methylation and promoted the destabilization of circPan3, and circPan3 could attenuate cardiomyocyte hypertrophy by targeting the miR-320-3p/HSP20 axis (214). METTL3 mediated the m6A modification of lncRNA H19 to alleviate cerebral ischemia-reperfusion injury by regulating the sphingosine-1-phosphate receptor 2/Toll-like receptor 4/NLR family pyrin domain containing 3 (NLRP3) signaling pathway (215). METTL14 mediated m6A-modified circZNF609, which regulated doxorubicin-induced cardiotoxicity by upregulating FTO (216).
m6A modification of ncRNAs in metabolic diseases
Diabetes-related diseases, obesity and nonalcoholic fatty liver disease are the most common metabolic diseases (Fig. 4). It has been reported that YTHDC2 mediated the m6A modification of circYTHDC2, which promoted dysfunction of vascular SMCs (VSMCs) and is an important target of metformin in preventing the progression of VSMC dysfunction in type 2 diabetes (217). METTL3 ameliorated diabetes-induced testicular damage by upregulating lncRNA TUG1/clusterin signaling (218). Diabetic retinopathy (DR) and diabetic nephropathy are common complications of diabetes. Fu et al (219) found that METTL3/YTHDC1 mediates the m6A modification and upregulation of lncRNA OGRU, which led to oxidative stress, inflammation and DR progression. Macrophage M1 regulatory DR is mediated by FTO-regulated m6A modification of LINC00342, LINC00667 and LNC00963 expression (220). WTAP mediated the m6A methylation of NEAT1, and subsequently NLRP3 inflammasome activation and dry eye disease in diabetes mellitus (221). In addition, Zheng et al (222) reported recently that dysregulated expression of circRNAs may be influenced by m6A modifications, and these circRNAs play significant roles in metabolism-associated fatty liver disease.
m6A modification of ncRNAs in neurological diseases
It has been reported that abnormal expression of m6A-related proteins also occurs in the nervous system, thereby affecting the development of neuroinflammation, AD, spinal cord injury (SCI) and cerebral ischemia-reperfusion injury (Fig. 5). For instance, Zhang et al (223) recently reported that m6A modification is enriched in circRNAs of neurons, and the m6A modification of circRNAs was reduced under oxygen-glucose deprivation and reoxygenation (OGD/R) injury conditions. Furthermore, through high-throughput sequencing, Zhang et al (224) identified eight m6A-modified circRNA that may be associated with the pathogenesis of AD. Furthermore, Liu et al (225) examined m6A modifications in SCI, revealing that 738 lncRNAs were differentially methylated (488 hypermethylated and 250 hypomethylated). In addition, Atrian et al (226) reported that tau-induced m6A methylation is a mechanistic driver of circMbl formation, and circMbl contributed to neurotoxicity and neurodegeneration. Electroacupuncture serum [serum was obtained from rats that were received electroacupuncture treatment 3 times at 'Renzhong' (GV26) and 'Baihui' (GV20) acupoints] alleviates OGD/R-induced astrocyte damage by regulating aquaporin 4 via m6A methylation of lncRNA MALAT1 (227).
Discussion
Various studies have shown the potential clinical value of m6A-modified ncRNAs as diagnostic biomarkers and prognostic indicators. It has been reported that the expression of m6A-modified circCUX1 was significantly upregulated in hypopharyngeal squamous cell carcinoma, and correlated with primary tumor size, lymph node metastasis, distant metastasis and tumor node metastasis stage, and its high expression indicated poor overall survival and poor disease-free survival (129). Furthermore, m6A-modified ABHD11-AS1 was found to be upregulated in human CRC tissues and related to poor prognosis (65). In addition, m6A-modified circCDYL existed in a stable form in HCC-derived exosomes, and was indicated to be a promising early diagnostic biomarker with an area under the curve of 0.896 (79). The distinct expression patterns of these novel ncRNA-derived peptides and proteins also offer considerable diagnostic potential. For instance, the serum levels of m6A-modified lncRNA AFAP1-AS1-encoded lncRNA AFAP1-AS1 translated mitochondrial-localized peptide were elevated in patients with non-small cell lung cancer (NSCLC) and associated with a poorer prognosis (190). The expression profiles of lncRNA-encoded microproteins in extracellular vesicles from patients with glioma differ from those in healthy donors (225). The high expression of circMAP3K4-455aa, a novel peptide encoded by m6A-modified circMAP3K4, predicts a worse prognosis for patients with HCC (17). Similarly, circMET encodes a 404-aa MET variant (MET404), and high MET404 expression was associated with poor prognosis in patients with glioblastoma (197).
The recent studies on m6A regulators and ncRNA-derived peptides render them promising therapeutic targets for numerous diseases, including malignant cancers. In esophageal squamous cell carcinoma, increasing m6A modification of circCREBBP could enhance the radiosensitivity of tumor cells (228). In CRC, ALKBH5 directly demethylates lncRNA CARMN, thereby suppressing the degradation of lncRNA CARMN and preserving lncRNA CARMN expression, and upregulated CARMN promoted tumor progression (92). Furthermore, Xinfeng capsule inhibited the progression of rheumatoid arthritis by modulating FTO-mediated m6A modification of lncRNA ENST00000619282 (229). These results indicated that modulating the activity of m6A-related enzymes, thereby regulating the m6A modification of target genes, has a critical role in disease treatment. A phase II study of bisantrene (a FTO inhibitor) in patients with relapsed/refractory acute myeloid leukemia showed that it achieved a partial remission, resulting in an overall response rate of 40% (230). Preclinical studies about METTL3 and METTL14 show promise in inhibiting tumor growth via direct anti-tumor effects and anti-cancer immune responses (231-233), and STC-15, a small-molecule inhibitor of METTL3, now has entered Phase I clinical trials (234). On the other hand, certain ncRNA-derived peptides have been reported to have special roles in disease treatment. For instance, a 188-aa peptide encoded by hsa_circRNA_103820 suppresses cell viability, induces apoptosis and inhibits cell migration and invasion in lung cancer (18). In addition, a tumor suppressor protein encoded by circKEAP1 inhibited stemness and metastasis by promoting vimentin proteasomal degradation and activating anti-tumor immunity in osteosarcoma (204). SPECC1-415aa, encoded by circSPECC1, inhibits the binding of annexin A1 (ANXA1) to EGFR by competitively binding to ANXA2, thereby preventing EGFR and AKT phosphorylation and restoring the sensitivity of temozolomide (TMZ)-resistant glioblastoma cells to TMZ (203). Although several ncRNA-encoded peptides have demonstrated tumor-suppressive functions, critical questions remain regarding their clinical applications. These include concerns about the feasibility of large-scale in vitro production and whether these cancer-suppressive micro-peptides can effectively target tumor cells upon injection. Future research should focus on unraveling the regulatory mechanisms underlying their expression and investigating how they exert their tumor-suppressing effects.
However, the use of ncRNAs or ncRNA-derived peptides for disease diagnosis or target therapy remains constrained by challenges. First, the roles of certain m6A-modified ncRNAs are conflicting. For instance, m6A-modified lncRNA MEG3 has been reported to suppress the proliferation, migration and invasion of HCC (235), while it promoted tumorigenesis and metastasis of NSCLC (104). Furthermore, it is difficult to detect m6A-modified ncRNAs or their encoded peptides in clinical samples. However, certain studies reported the existence of these ncRNAs or peptides in biofluids, such as blood and urine, indicating it is accessibility that using ncRNAs for testing diagnostic. For instance, m6A-modified circSLC38A1 was identified in serum exosomes of patients with bladder cancer and could distinguish patients with bladder cancer from healthy individuals with a diagnostic accuracy of 0.878 (236). Furthermore, Li et al (59) reported that circTRIM1 encoded TRIM1-269aa, which can be detected in exosomes from patients with triple-negative breast cancer. In addition, standard hybridization-based techniques cannot be applied for sensing m6A in RNAs and the development of new methods for accurate and sensitive profiling of locus-specific m6A in RNAs remains a great challenge. Liu et al (237) recently constructed a hierarchical DNA circuit for single-molecule profiling of locus-specific m6a-MALAT1 in clinical tissues. Finally, the dynamic nature of m6A modification makes it difficult to establish causal relationships in vivo. However, it has been reported that the transcriptome-wide m6A methylome was dynamically altered during initial diagnosis and relapse and can be monitored by methylated RNA immunoprecipitation next-generation sequencing (238). Recently, Song et al (38) presented a method termed proximity hybridization followed by primer exchange amplification, which could image m6A methylation sites concurrently in multiple cell types, revealing cell-to-cell variability in expression levels.
Conclusions
In conclusion, this review provided a comprehensive overview of the current understanding of m6A modification in ncRNAs, including miRNAs, lncRNAs and circRNAs. It explored how m6A modification regulates their biogenesis, maturation, localization and stability. Importantly, this review introduced the identification of peptides derived from m6A-modified ncRNAs. Furthermore, the diverse roles of m6A-modified ncRNAs and their encoded peptides in tumorigenesis, cardiovascular disorders, metabolic diseases and neurological diseases were discussed. It also highlights their potential clinical applications in cancer diagnosis, disease prediction and targeted therapy, offering new insights and perspectives to advance research in this field.
Availability of data and materials
Not applicable.
Authors' contributions
QY performed the literature search. QY and YL prepared the first draft of the manuscript. WS wrote and edited the manuscript. JL and DY drew the figures. WS and HS prepared the tables and were responsible for revising the manuscript. QY, WS and WC obtained funding support. All authors reviewed the manuscript, and have read and approved of 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.
α-ketoglutarate-dependent dioxygenase alk B homolog 5
ESCC
esophageal squamous cell carcinoma
TAM
tumour-associated macrophage
OC
ovarian cancer
BC
breast cancer
GC
gastric cancer
I/R
ischemia/reperfusion
EV
extracellular vesicle
AGO2
Argonaute 2
LPS
lipopolysaccharide
Acknowledgements
Not applicable.
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Structural schematic representation of the reversible and dynamic post-transcriptional m6A modification of RNA. In the nucleus, methyltransferases and demethylases regulate the m6A modifications of target mRNAs. m6A readers modulate the splicing and transport of target mRNAs. In the cytoplasm, different m6A readers control the stability, degradation, localization and translation of mRNAs through distinct mechanisms. WTAP, Wilms' tumor 1-associated protein; ZC3H13, zinc finger CCCH-type containing 13; METTL3/14/16, methyltransferase-like 3/14/16; VIRMA, vir like m6A methyltransferase associated protein; FTO, fat mass and obesity-associated protein; ALKBH5, α-ketoglutarate-dependent dioxygenase alk B homolog 5; hnRNPC/hnRNPG/hnRNPA2B1, heterogeneous nuclear ribonucleoprotein C/G/A2B1; IGF2BP1/2/3, insulin-like growth factor 2 mRNA-binding protein 1/2/3; YTHDF1/2/3, YTHDC1/2, YTH N6-methyladenosine RNA binding protein F1/2/3, C1/2.
Effects and functions of m6A modification on ncRNAs (lncRNAs and circRNAs). (A) m6A modification facilitates the biogenesis of ncRNAs. (B) m6A readers promote the cytoplasmic export of ncRNAs. (C) m6A readers mediate the nuclear retention or translocation of ncRNAs. (D) m6A readers regulate the sorting of ncRNAs into exosomes. (E) m6A readers control the stability or degradation of ncRNAs. (F) m6A-dependent translation of ncRNAs. WTAP, Wilms' tumor 1-associated protein; lncRNA, long noncoding RNA; METTL3/14, methyltransferase-like 3/14; hnRNPC/hnRNPA2B1, heterogeneous nuclear ribonucleoprotein C/A2B1; IGF2BP1/2/3, insulin-like growth factor 2 mRNA-binding protein 1/2/3; YTHDF1/2/3, YTH N6-methyladenosine RNA binding protein F1/2/3, C1/2; eIF4Gs, eukaryotic translation initiation factor 4 gamma.
Effects of m6A-modified ncRNAs in the pathological processes of cardiovascular diseases. (A) m6A-modified ncRNAs facilitate the progression of atherosclerosis. (B) Role of m6A-modified ncRNAs in regulating the viability of cardiomyocytes. (C) m6A-modified ncRNAs facilitate the progression of myocardial ischemia-reperfusion injury. WTAP, Wilms' tumor 1-associated protein; METTL3/14, methyltransferase-like 3/14; YTHDF2/C1, YTH N6-methyladenosine RNA binding protein F2/C1; hnRNP F, heterogeneous nuclear ribonucleoprotein F; EIF4A3, eukaryotic translation initiation factor 4A3; Sirt1, sirtuin 1; FOXO1, forkhead box O1; NEAT1, nuclear paraspeckle assembly transcript 1; FTO, fat mass and obesity-associated protein; KLF4, KLF transcription factor 4; NLRP3, NLR family pyrin domain containing 3; RIPK1, receptor interacting serine/threonine kinase 1, ROS, reactive oxygen species; DOX, doxorubicin; SNHG1/8, small nucleolar RNA host gene 1/8; PTBP1, polypyrimidine tract binding protein 1; ALAS2, 5′-aminolevulinate synthase 2; OPA1, OPA1 mitochondrial dynamin like GTPase.
Effects of m6A-modified ncRNAs in the pathological processes of metabolic diseases. (A) m6A-modified ncRNAs facilitate the progression of gestational diabetes mellitus. (B) Role of m6A-modified ncRNAs in regulating obesity. (C) m6A-modified ncRNAs facilitate the progression of diabetic cardiomyopathy. (D) m6A-modified ncRNAs facilitate the progression of diabetic retinopathy. (E) m6A-modified ncRNAs facilitate the progression of diabetic nephropathy. METTL3/14, methyltransferase-like 3/14; lncRNA, long noncoding RNA; FOXO1, forkhead box O1; XIST, X inactive specific transcript; BRG1, SBP (S-ribonuclease binding protein) family protein; TINCR, TINCR ubiquitin domain containing; NLRP3, NLR family pyrin domain containing 3; SNHG7, small nucleolar RNA host gene 7; KHSRP, KH-type splicing regulatory protein; MKL1, kinase MKL1 MAPK-like protein; ALKBH5, α-ketoglutarate-dependent dioxygenase alk B homolog 5; PTBP1, polypyrimidine tract binding protein 1; RAB3B, member RAS oncogene family; GLUT4, solute carrier family 2 (facilitated glucose transporter), member 4; TUG1, taurine up-regulated 1; LIN28B, lin-28 homolog B; MAPK1, mitogen-activated protein kinase 1.
Effects of m6A-modified ncRNAs in the pathological processes of neurological diseases. (A) m6A-modified ncRNAs regulate the development and inflammation of the central nervous system. (B) m6A-modified ncRNAs regulate the viability and function of neuronal cells. (C) m6A-modified ncRNAs facilitate the progression of cerebral ischemia-reperfusion injury. (D) m6A-modified ncRNAs facilitate the progression of Alzheimer➢s disease.
Effects of m6A modification on ncRNA stability.
ncRNAs
m6A regulator
Stability
Function
(Refs.)
LncRNA PVT1
ALKBH5
Decreased
Regulates OC growth and lung cancer metastasis
(102,103)
LncRNA MEG3
HNRNPA2B1
Decreased
Facilitates tumorigenesis of NSCLC
(104)
LncRNA NEAT1
ALKBH5, METTL3
Enhanced
Facilitates immunosuppression and cerebral I/R injury
(105,106)
LncRNA MALAT1
METTL3/HuR, METTL3, IGF2BP2
Enhanced
Promotes the malignant progression of glioma, OS and NSCLC
(107-109)
LncRNA ZFAS1
IGF2BP2, METTL3
Enhanced
Promotes mitochondrial energy metabolism and affects autophagy and progression of NPC
(110,111)
LncRNA DANCR
METTL3, IGF2BP2
Enhanced
Contributes to OS, pancreatic cancer and acute myeloid leukemia progression
(112-114)
LINC00958
METTL3, KIAA1429
Enhanced
Promotes BC tumorigenesis, HCC lipogenesis and progression, and accelerates GC aerobic glycolysis
(115-117)
KCNQ1OT1
IGF2BP1, MELLL3, ALKHB5
Enhanced
Promotes cardiomyocyte ferroptosis, doxorubicin resistance in BC and the development of LSCC
(118-120)
FOXD2-AS1
METTL3, WTAP
Enhanced
Accelerates cervical cancer and OS progression
(121,122)
LncRNA PCAT6
METTL3/IGF2BP2
Enhanced
Promotes bone metastasis in prostate cancer
(123)
THAP7-AS1
METTL3/IGF2BP1
Enhanced
Promotes GC growth, invasion and metastasis
(124)
LncRNA PTTG3P
METTL3/IGF2BP2
Enhanced
Contributes to CRC proliferation
(125)
DLGAP1-AS1
WTAP
Enhanced
Enhances the resistance of BC to adriamycin
(126)
LncRNA CASC9
IGF2BP2
Enhanced
Accelerates glioblastoma aerobic glycolysis
(127)
ABHD11-AS1
METTL3
Enhanced
Enhances the Warburg effect of NSCLC
(128)
CircCUX1
METTL3
Enhanced
Confers radioresistance of hypopharyngeal squamous cell carcinoma
(129)
CircARHGAP12
IGF2BP2
Enhanced
Promotes cervical cancer progression
(130)
CircGLIS3
METTL3
Enhanced
Promotes cell proliferation and invasion.
(131)
CircDLC1
METTL3
Enhanced
Suppresses the proliferation of glioma
(132)
CircRPS6KC1
METTL3/YTHDF1
Enhanced
Regulate cellular senescence
(133)
CircASXL1
METTL3/IGF2BP1
Enhanced
Promotes proliferation and migration of OC
(134)
Circ_0006168
METTL3/IGF2BP2
Enhanced
Promotes EMT process in ESCC
(135)
CircPAPPA2
METTL14/IGF2BP3
Decreased
Regulates the pathogenesis of preeclampsia
(136)
CircCCDC134
ALKBH5
Decreased
Facilitates cervical cancer metastasis
(137)
CircHIPK2
YTHDF2
Decreased
Alleviates microglia activation
(138)
CircAFF2
ALKBH5/YTHDF2
Decreased
Enhances radiosensitivity of colorectal cancer
(139)
CircMPP1
YTHDC1
Decreased
Maintains trophoblasts function
(140)
Circ_0003979
RBM15/YTHDF2
Decreased
Inhibits HCC tumorigenesis
(141)
CircIRF2
YTHDF2
Decreased
Suppresses liver fibrosis
(142)
OS, osteosarcoma; OC, ovarian cancer; NSCLS, non-small cell lung cancer; NPC, nasopharyngeal carcinoma; BC, breast cancer; HCC, hepatocellular carcinoma; GC, gastric cancer; LSCC, laryngeal squamous cell carcinoma; CRC, colorectal cancer; ALKBH5, α-ketoglutarate-dependent dioxygenase alk B homolog 5; HNRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; METTL3/14, methyltransferase 3/14; HuR, also known as Elavl1, ELAV like RNA binding protein 1; IGF2BP1/2/3, insulin-like growth factor 2 mRNA binding protein 1/2/3; KIAA1429, also known as vir-like m6A methyltransferase associated protein; WTAP, Wilms' tumor 1-associated protein; YTHDF1/2, YTH N6-methyladenosine RNA binding protein F1/2, YTHDC1, YTH N6-methyladenosine RNA binding protein C1; RBM15, RNA binding motif protein 15.
Effects of m6A modification on ncRNA localization.