Revisão Acesso aberto Revisado por pares

Recent advances in crosstalk between N6-methyladenosine (m6A) modification and circular RNAs in cancer

2022; Cell Press; Volume: 27; Linguagem: Inglês

10.1016/j.omtn.2022.01.013

ISSN

2162-2531

Autores

Xin Huang, Haoyu Guo, Lutong Wang, Lingkai Yang, Zengwu Shao, Weiyue Zhang,

Tópico(s)

HVDC Systems and Fault Protection

Resumo

N6-methyladenosine (m6A), as the most common RNA modification, plays a vital role in the development of cancers. Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA molecules. Recently, m6A modification has been identified as performing biological functions for regulating circRNAs. Increasing evidence also shows that circRNAs are involved in cancer progression by targeting m6A regulators. In this review, we describe the functional crosstalk between m6A and circRNAs, and illustrate their roles in cancer development. m6A methylation mediates the biogenesis, stability, and cytoplasmic export of circRNAs in different cancer types. Moreover, circRNAs regulate the expression of m6A regulators, participate in the degradation of m6A regulators, and regulate the m6A modification of target mRNAs. Finally, we discuss the potential applications and future research directions of m6A modification and circRNAs in cancer. Further understanding of the biological roles of m6A and circRNAs will provide new insight into the diagnosis and treatment of cancer patients. N6-methyladenosine (m6A), as the most common RNA modification, plays a vital role in the development of cancers. Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA molecules. Recently, m6A modification has been identified as performing biological functions for regulating circRNAs. Increasing evidence also shows that circRNAs are involved in cancer progression by targeting m6A regulators. In this review, we describe the functional crosstalk between m6A and circRNAs, and illustrate their roles in cancer development. m6A methylation mediates the biogenesis, stability, and cytoplasmic export of circRNAs in different cancer types. Moreover, circRNAs regulate the expression of m6A regulators, participate in the degradation of m6A regulators, and regulate the m6A modification of target mRNAs. Finally, we discuss the potential applications and future research directions of m6A modification and circRNAs in cancer. Further understanding of the biological roles of m6A and circRNAs will provide new insight into the diagnosis and treatment of cancer patients. According to recent global statistics, cancer is still an important factor that influences human health.1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J. Clin. 2020; 70: 7-30Crossref PubMed Scopus (10876) Google Scholar N6-methyladenosine (m6A), as the most common RNA modification, has attracted increasing attention in the field of cancer development.2Lan Q. Liu P.Y. Haase J. Bell J.L. Hüttelmaier S. Liu T. The critical role of RNA m(6)A methylation in cancer.Cancer Res. 2019; 79: 1285-1292Crossref PubMed Scopus (308) Google Scholar,3Liu J. Harada B.T. He C. 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Cancer. 2020; 19: 22Crossref PubMed Scopus (181) Google Scholar; however, studies on how circRNAs are regulated before exerting specific biological functions are still limited.18Meng J. Chen S. Han J.X. Qian B. Wang X.R. Zhong W.L. Qin Y. Zhang H. Gao W.F. Lei Y.Y. et al.Twist1 regulates vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma.Cancer Res. 2018; 78: 4150-4162Crossref PubMed Scopus (173) Google Scholar m6A modification has been discovered in various noncoding RNAs (ncRNAs) including microRNAs, long ncRNAs (lncRNAs), circRNAs,19Zhang L. Hou C. Chen C. Guo Y. Yuan W. Yin D. Liu J. Sun Z. The role of N(6)-methyladenosine (m(6)A) modification in the regulation of circRNAs.Mol. Cancer. 2020; 19: 105Crossref PubMed Scopus (89) Google Scholar ribosomal RNAs (rRNAs), and small nuclear RNAs (snRNAs). m6A modification has been found to be essential for the metabolism and functions of ncRNAs. For example, Zhang et al. summarized the role of m6A modification in the regulation and function of circRNAs, in which m6A modification regulates circRNA translation and degradation and modifies circRNA in innate immunity.19Zhang L. Hou C. Chen C. Guo Y. Yuan W. Yin D. Liu J. Sun Z. The role of N(6)-methyladenosine (m(6)A) modification in the regulation of circRNAs.Mol. Cancer. 2020; 19: 105Crossref PubMed Scopus (89) Google Scholar More interestingly, ncRNAs also participate in the regulation of m6A modification, thereby regulating their target mRNAs. Previous studies have investigated the crosstalk between m6A modification and ncRNAs in the development and treatment of cancer.20Huang H. Weng H. Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer.Cancer Cell. 2020; 37: 270-288Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 21Yi Y.C. Chen X.Y. Zhang J. Zhu J.S. Novel insights into the interplay between m(6)A modification and noncoding RNAs in cancer.Mol. Cancer. 2020; 19: 121Crossref PubMed Scopus (79) Google Scholar, 22Chen Y. Lin Y. Shu Y. He J. Gao W. Interaction between N(6)-methyladenosine (m(6)A) modification and noncoding RNAs in cancer.Mol. Cancer. 2020; 19: 94Crossref PubMed Scopus (75) Google Scholar, 23Dai F. Wu Y. Lu Y. An C. Zheng X. Dai L. Guo Y. Zhang L. Li H. Xu W. et al.Crosstalk between RNA m(6)A modification and non-coding RNA contributes to cancer growth and progression.Mol. Ther. Nucleic Acids. 2020; 22: 62-71Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 24Ma S. Chen C. Ji X. Liu J. Zhou Q. Wang G. Yuan W. Kan Q. Sun Z. The interplay between m6A RNA methylation and noncoding RNA in cancer.J. Hematol. Oncol. 2019; 12: 121Crossref PubMed Scopus (180) Google Scholar However, the roles of m6A and circRNAs in cancer have not been reviewed comprehensively. In this review, we describe the functional crosstalk between m6A and circRNAs in cancers. m6A methylation mediates the biogenesis, stability, and cytoplasmic export of circRNAs in different cancer types. Moreover, circRNAs regulate the expression of m6A regulators, participate in the degradation of m6A regulators, and regulate the m6A modification of target mRNAs. Finally, we investigate the biological roles of m6A and circRNAs in cancer development, which promote the clinical application of m6A and circRNAs for cancer patients. m6A modification is regulated by m6A regulators including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). m6A writers are regarded as the m6A methylase complex and include methyltransferase-like 3 (METTL3),25Yue B. Song C. Yang L. Cui R. Cheng X. Zhang Z. Zhao G. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer.Mol. Cancer. 2019; 18: 142Crossref PubMed Scopus (223) Google Scholar methyltransferase-like 14 (METTL14),26Yang X. Zhang S. He C. Xue P. Zhang L. He Z. Zang L. Feng B. Sun J. Zheng M. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST.Mol. Cancer. 2020; 19: 46Crossref PubMed Scopus (169) Google Scholar Wilms' tumor-associated protein (WTAP),27Chen 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. 2019; 18: 127Crossref PubMed Scopus (230) Google Scholar RNA-binding motif protein 15 (RBM15) and its paralog RBM15B,28Wang X. Tian L. Li Y. Wang J. Yan B. Yang L. Li Q. Zhao R. Liu M. Wang P. et al.RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent.J. Exp. Clin. 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Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex.RNA. 2018; 24: 499-512Crossref PubMed Scopus (173) Google Scholar and RBM15/15B can recruit the complex to methylate specific sites through interaction with METTL3 in a WTAP-dependent manner.31Patil D.P. Chen C.K. Pickering B.F. Chow A. Jackson C. Guttman M. Jaffrey S.R. m(6)A RNA methylation promotes XIST-mediated transcriptional repression.Nature. 2016; 537: 369-373Crossref PubMed Scopus (775) Google Scholar The molecular function of KIAA1429 in the m6A methylase complex remains unknown.32Schwartz S. Mumbach M.R. Jovanovic M. Wang T. Maciag K. Bushkin G.G. 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. 2014; 8: 284-296Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar As a dynamic and reversible RNA modification, m6A can be regulated by m6A writers and erasers, which exhibit the complexity of epigenetic modifications. Two demethylases, alkB homolog 5 (ALKBH5) and fat mass and obesity-associated protein (FTO), have been identified as m6A erasers.33Mauer J. Sindelar M. Despic V. Guez T. Hawley B.R. Vasseur J.J. Rentmeister A. Gross S.S. Pellizzoni L. Debart F. et al.FTO controls reversible m(6)Am RNA methylation during snRNA biogenesis.Nat. Chem. Biol. 2019; 15: 340-347Crossref PubMed Scopus (120) Google Scholar,34Yu H. Yang X. Tang J. Si S. Zhou Z. Lu J. Han J. Yuan B. Wu Q. Lu Q. et al.ALKBH5 inhibited cell proliferation and sensitized bladder cancer cells to cisplatin by m6A-CK2α-mediated glycolysis.Mol. Ther. Nucleic Acids. 2021; 23: 27-41Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Moreover, m6A modifications in an RNA structure might be selectively recognized by some RNA-binding proteins (RBPs), named m6A readers. The m6A readers mainly consist of the YT521-B homology (YTH) domain-containing protein family (YTHDC1-2, YTHDF1-3),35Liu X. Qin J. Gao T. Li C. He B. Pan B. Xu X. Chen X. Zeng K. Xu M. et al.YTHDF1 facilitates the progression of hepatocellular carcinoma by promoting FZD5 mRNA translation in an m6A-dependent manner.Mol. Ther. Nucleic Acids. 2020; 22: 750-765Abstract Full Text PDF PubMed Scopus (33) Google Scholar the heterogeneous nuclear ribonucleoprotein (HNRNP) family (HNRNPA2B1, HNRNPC, and HNRNPG), and IGF2BPs.36Huang H. Weng H. Sun W. Qin X. Shi H. Wu H. Zhao B.S. Mesquita A. Liu C. Yuan C.L. et al.Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.Nat. Cell Biol. 2018; 20: 285-295Crossref PubMed Scopus (844) Google Scholar However, a new understanding of these proteins has led to the reversal of early concepts regarding the reading, writing, and erasing of m6A.37Meyer K.D. Jaffrey S.R. Rethinking m(6)A readers, writers, and erasers.Annu. Rev. Cell Dev. Biol. 2017; 33: 319-342Crossref PubMed Scopus (494) Google Scholar In this review, we summarize recent advances in research on m6A and circRNAs, and we highlight how these new findings have reshaped our understanding of how m6A is regulated by circRNAs in cancer. Genes can generate different circRNAs via alternative circularization,38Salzman J. Gawad C. Wang P.L. Lacayo N. Brown P.O. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types.PLoS one. 2012; 7: e30733Crossref PubMed Scopus (1594) Google Scholar leading to the diversity of circRNAs. Another novel characteristic of circRNAs is that they cannot be degraded by exonucleases and are more stable than linear RNAs.39Memczak S. Jens M. Elefsinioti A. Torti F. Krueger J. Rybak A. Maier L. Mackowiak S.D. Gregersen L.H. Munschauer M. et al.Circular RNAs are a large class of animal RNAs with regulatory potency.Nature. 2013; 495: 333-338Crossref PubMed Scopus (4716) Google Scholar Studies have revealed that circRNAs are highly conserved in evolution between different species. The last characteristic of circRNAs is that their expression can change in different tissues and different growth stages. Therefore, circRNAs can function as ideal biomarkers of diseases.40You X. Vlatkovic I. Babic A. Will T. Epstein I. Tushev G. Akbalik G. Wang M. Glock C. Quedenau C. et al.Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity.Nat. Neurosci. 2015; 18: 603-610Crossref PubMed Scopus (698) Google Scholar,41Su M. Xiao Y. Ma J. Tang Y. Tian B. Zhang Y. Li X. Wu Z. Yang D. Zhou Y. et al.Circular RNAs in cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers.Mol. Cancer. 2019; 18: 90Crossref PubMed Scopus (200) Google Scholar Regarding the biological functions of circRNAs, the most classical network is that circRNAs act as competing endogenous RNAs (ceRNAs). With miRNA response elements, circRNAs can function as "miRNA sponges" to bind specific miRNAs to negatively regulate their activity.42Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen B. Damgaard C.K. Kjems J. Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (4703) Google Scholar Furthermore, circRNAs can also exert protein binding abilities by interacting with some RBPs to inhibit their function or transport.43Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1677) Google Scholar Recent studies have shown the abnormal expression of circRNAs in various cancers.44Shan C. Zhang Y. Hao X. Gao J. Chen X. Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer.Mol. Cancer. 2019; 18: 136Crossref PubMed Scopus (95) Google Scholar, 45Sun J. Li B. Shu C. Ma Q. Wang J. Functions and clinical significance of circular RNAs in glioma.Mol. Cancer. 2020; 19: 34Crossref PubMed Scopus (75) Google Scholar, 46Wang Y. Zhang Y. Wang P. Fu X. Lin W. Circular RNAs in renal cell carcinoma: implications for tumorigenesis, diagnosis, and therapy.Mol. Cancer. 2020; 19: 149Crossref PubMed Scopus (33) Google Scholar The expression and function of circRNAs in cancer might be partly attributed to their epigenetic modification, and m6A modification is the first notable role (Figure 1). METTL3 is the key component of the methyltransferase complex and plays a vital role in cancers. A study by Li et al.47Li Z. Yang H.Y. Dai X.Y. Zhang X. Huang Y.Z. Shi L. Wei J.F. Ding Q. CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression.Int. J. Biol. Sci. 2021; 17: 1178-1190Crossref PubMed Scopus (12) Google Scholar investigated the biological function of circRNAs derived from METTL3 in breast cancer. In their study, METTL3, as the host gene of circMETTL3, was found to regulate circMETTL3 expression in an m6A-dependent manner. They further downregulated METTL14 or FTO to modify the m6A level of circMETTL3. Downregulated METTL14 reduced circMETTL3 expression and increased pre-METTL3 expression, while decreased FTO expression caused the opposite effect. Their study provided novel insight into the relationship between circRNAs and the corresponding host genes. Chen et al.48Chen C. Yuan W. Zhou Q. Shao B. Guo Y. Wang W. Yang S. Guo Y. Zhao L. Dang Q. et al.N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization.Theranostics. 2021; 11: 4298-4315Crossref PubMed Scopus (34) Google Scholar found that METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modification in colorectal cancer (CRC). Researchers have reported that the alternative splicing of RNA can be regulated by m6A modification.20Huang H. Weng H. Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer.Cancer Cell. 2020; 37: 270-288Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar Moreover, circRNAs are derived from their parental pre-mRNAs by alternative splicing.49Kramer M.C. Liang D. Tatomer D.C. Gold B. March Z.M. Cherry S. Wilusz J.E. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins.Genes Dev. 2015; 29: 2168-2182Crossref PubMed Scopus (291) Google Scholar KIAA1429 is an important part of the m6A methyltransferase complex. Liu et al.50Liu H. Lan T. Li H. Xu L. Chen X. Liao H. Chen X. Du J. Cai Y. Wang J. et al.Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR.Theranostics. 2021; 11: 1396-1411Crossref PubMed Scopus (34) Google Scholar aimed to identify KIAA1429-regulated circRNAs in hepatocellular carcinoma (HCC) via RNA sequencing and methylated RNA immunoprecipitation sequencing (MeRIP-seq). They found that the regulatory effect of KIAA1429 in the production of circDLC1 is involved in the processing of preDLC1. The detailed mechanism of KIAA1429-mediated alternative splicing during the processing of preDLC1 into circDLC1 requires further investigation. Rao et al.51Rao X. Lai L. Li X. Wang L. Li A. Yang Q. N(6) -methyladenosine modification of circular RNA circ-ARL3 facilitates hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305.IUBMB Life. 2021; 73: 408-417Crossref PubMed Scopus (22) Google Scholar also reported that the m6A reader YTHDC1 bound to m6A-modified circ-ARL3 and favored its reverse splicing and biogenesis in the development of HBV + HCC. Wu et al.52Wu P. Fang X. Liu Y. Tang Y. Wang W. Li X. Fan Y. N6-methyladenosine modification of circCUX1 confers radioresistance of hypopharyngeal squamous cell carcinoma through caspase1 pathway.Cell Death Dis. 2021; 12: 298Crossref PubMed Scopus (29) Google Scholar found that METTL3 mediated m6A methylation and stabilized the expression of circCUX1, which is involved in radiotherapy tolerance in hypopharyngeal squamous cell carcinoma (HPSCC) patients. In cervical cancer (CC), Chen et al.53Chen Z. Ling K. Zhu Y. Deng L. Li Y. Liang Z. circ0000069 promotes cervical cancer cell proliferation and migration by inhibiting miR-4426.Biochem. Biophys. Res. Commun. 2021; 551: 114-120Crossref PubMed Scopus (9) Google Scholar revealed that circ0000069 was upregulated partially due to m6A modification, which maintained the stability of circ0000069. Xu et al.54Xu J. Wan Z. Tang M. Lin Z. Jiang S. Ji L. Gorshkov K. Mao Q. Xia S. Cen D. et al.N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling.Mol. Cancer. 2020; 19: 163Crossref PubMed Scopus (79) Google Scholar found that the m6A level of circRNA-SORE was increased in sorafenib-resistant cells, and circRNA-SORE expression was downregulated when its m6A modification was inhibited. Accordingly, m6A regulates circRNA-SORE expression by increasing its stability; however, no remarkable differences in the expression levels of m6A-related proteins were found in sorafenib-resistant cells. The underlying mechanisms of increased circRNA-SORE m6A levels in sorafenib-resistant cells should be further illustrated. Internal ribosome entry sites (IRESs) are sequences that can activate a cap-independent translation process by binding ribosomes with RNAs including circRNAs.55Wang Y. Wang Z. Efficient backsplicing produces translatable circular mRNAs.RNA. 2015; 21: 172-179Crossref PubMed Scopus (431) Google Scholar Recently, another cap-independent pathway driven by m6A was reported by Yang et al.56Yang Y. Fan X. Mao M. Song X. Wu P. Zhang Y. Jin Y. Yang Y. Chen L.L. Wang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (936) Google Scholar In response to environmental stress, circRNAs containing m6A motifs are activated by eIF4G2 and YTHDF3. Moreover, methyltransferases (such as METTL3/14) can enhance the translation process, while demethylase FTO inhibits it.56Yang Y. Fan X. Mao M. Song X. Wu P. Zhang Y. Jin Y. Yang Y. Chen L.L. Wang Y. et al.Extensive translation of circular RNAs driven by N(6)-methyladenosine.Cell Res. 2017; 27: 626-641Crossref PubMed Scopus (936) Google Scholar In particular, Legnini et al. indicated that the above pathways may have some connections since they found that the m6A methylation level was enhanced in some IRES-activated protein-coding circRNAs.57Legnini I. Di Timoteo G. Rossi F. Morlando M. Briganti F. Sthandier O. Fatica A. Santini T. Andronache A. Wade M. et al.Circ-ZNF609 is a circular RNA that can Be translated and functions in myogenesis.Mol. Cell. 2017; 66: 22-37 e29Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar,58Zhao X. Yang Y. Sun B.F. Shi Y. Yang X. Xiao W. Hao Y.J. Ping X.L. Chen Y.S. Wang W.J. et al.FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.Cell Res. 2014; 24: 1403-1419Crossref PubMed Scopus (627) Google Scholar These results reveal that m6A methylation mediates circRNA translation through delicate mechanisms. However, the role of m6A methylation in the translation of circRNAs has not been thoroughly investigated in cancer to date. CircRNAs are more stable due to their single-stranded covalently closed structure. It has been reported that circRNAs are less likely to degrade than their corresponding parental linear RNAs. However, how circRNAs are degraded and what factors accelerate their degradation remain largely unknown.19Zhang L. Hou C. Chen C. Guo Y. Yuan W. Yin D. Liu J. Sun Z. The role of N(6)-methyladenosine (m(6)A) modification in the regulation of circRNAs.Mol. Cancer. 2020; 19: 105Crossref PubMed Scopus (89) Google Scholar A previous study by Wang et al.59Wang X. Lu Z. Gomez A. Hon G.C. Yue Y. Han D. Fu Y. Parisien M. Dai Q. Jia G. et al.N6-methyladenosine-dependent regulation of messenger RNA stability.Nature. 2014; 505: 117-120Crossref PubMed Scopus (1964) Google Scholar revealed that m6A can regulate mRNA degradation via selective recognition by YTHDF2. They further developed a mechanistic model that indicated that C-YTHDF2 selectively binds to m6A-containing mRNA. In addition, N-YTHDF2 commits to degradation by localizing the YTHDF2-m6A-mRNA complex to more specialized mRNA decay sites. On this basis, Du et al.60Du H. Zhao Y. He J. Zhang Y. Xi H. Liu M. Ma J. Wu L. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.Nat. Commun. 2016; 7: 12626Crossref PubMed Scopus (580) Google Scholar further corrected the model and revealed the mechanism of m6A-containing RNA degradation mediated by YTHDF2. They demonstrated that N-YTHDF2 interacts directly with the SH domain of CNOT1 to recruit the CCR4-NOT complex, consequently accelerating the deadenylation of m6A-containing RNAs, which is important for the YTHDF2-mediated degradation of m6A-containing RNAs. Recently, it was reported that m6A-containing RNAs can be recognized and destabilized by the YTHDF2-HRSP12-RNase P/MRP axis. Park et al.61Park O.H. Ha H. Lee Y. Boo S.H. Kwon D.H. Song H.K. Kim Y.K. Endoribonucleolytic cleavage of m(6)A-containing RNAs by RNase P/MRP complex.Mol. Cell. 2019; 74: 494-507.e8Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar showed that YTHDF2 can target m6A positions in linear and circular RNAs and mediate the endoribonucleolytic cleavage of m6A-modified RNAs by RNase. In addition, if there are HRSP12-binding sites near the m6A positions, the cleavage will be more thorough and specifically downregulate the target RNAs. These investigations indicate that m6A may mediate the downregulation of circRNAs; however, no relevant studies have been reported in cancer. Further in-depth experiments should be designed to explore whether m6A methylation mediates the degradation of circRNAs in cancer. CircRNAs might play a role at specific sites in cells. Chen et al.62Chen R.X. Chen X. Xia L.P. Zhang J.X. Pan Z.Z. Ma X.D. Han K. Chen J.W. Judde J.G. Deas O. et al.N(6)-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis.Nat. Commun. 2019; 10: 4695Crossref PubMed Scopus (240) Google Scholar found that m6A of circNSUN2 increases cytoplasmic export in CRC. By functioning as the circNSUN2/IGF2BP2/HMGA2 complex in the cytoplasm, circNSUN2 could promote the stability of HMGA2 mRNA and the metastasis of CRC. In summary, m6A modification of circRNAs in cancer mainly includes (1) mediating the biogenesis of circRNAs, (2) maintaining the stability of circRNAs, and (3) promoting the cytoplasmic export of circRNAs (Table 1 and Figure 2). In this way, m6A modification in cancer regulates the biogenesis, expression, and function of circRNAs.Table 1m6A modification of circRNAs in cancerm6A regulatorcircRNACancer typeCell line typeMechanismCitationBiogenesis of circRNAMETTL3circMETTL3Breast cancerZR-75-1, SUM1315METTL3 as the host gene of circMETTL3 may regulate circMETTL3 expressionLi et al.47Li Z. Yang H.Y. Dai X.Y. Zhang X. Huang Y.Z. Shi L. Wei J.F. Ding Q. CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression.Int. J. Biol. Sci. 2021; 17: 1178-1190Crossref PubMed Scopus (12) Google ScholarMETTL3circ1662CRCHCT116, SW480METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modificationsChen et al.48Chen C. Yuan W. Zhou Q. Shao B. Guo Y. Wang W. Yang S. Guo Y. Zhao L. Dang Q. et al.N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization.Theranostics. 2021; 11: 4298-4315Crossref PubMed Scopus (34) Google ScholarKIAA1429circDLC1HCCHuh-7, SK-Hep1, SNU 449, HCC-LM9KIAA1429-mediated alternative splicing during the processing of preDLC1 into circDLC1Liu et al.50Liu H. Lan T. Li H. Xu L. Chen X. Liao H. Chen X. Du J. Cai Y. Wan

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