The role of RNA N6-methyladenosine methyltransferase in cancers
2021; Cell Press; Volume: 23; Linguagem: Inglês
10.1016/j.omtn.2020.12.021
ISSN2162-2531
AutoresJiali Huang, Zhenyao Chen, Xin Chen, Jun Chen, Zhixiang Cheng, Zhaoxia Wang,
Tópico(s)Cancer-related gene regulation
ResumoModification of eukaryotic RNA by methylation of adenosine residues to generate N6-methyladenosine (m6A) is a highly prevalent process. m6A is dynamically regulated during cell metabolism and embryo development, and it is mainly involved in various aspects of RNA metabolism, including RNA splicing, processing, transport from the nucleus, translation, and degradation. Accumulating evidence shows that dynamic changes to m6A are closely related to the occurrence and development of cancer and that methyltransferases, as key elements in the dynamic regulation of m6A, play a crucial role in these processes. Therefore, in this review, we describe the role of methyltransferases as m6A writers in cancer and summarize their potential molecular mechanisms of action. Modification of eukaryotic RNA by methylation of adenosine residues to generate N6-methyladenosine (m6A) is a highly prevalent process. m6A is dynamically regulated during cell metabolism and embryo development, and it is mainly involved in various aspects of RNA metabolism, including RNA splicing, processing, transport from the nucleus, translation, and degradation. Accumulating evidence shows that dynamic changes to m6A are closely related to the occurrence and development of cancer and that methyltransferases, as key elements in the dynamic regulation of m6A, play a crucial role in these processes. Therefore, in this review, we describe the role of methyltransferases as m6A writers in cancer and summarize their potential molecular mechanisms of action. According to central genetic dogma, genetic information is transferred from DNA to RNA and then from RNA to protein by the transcription and translation processes, respectively. Epigenetic modification mainly involves DNA, RNA, and proteins. During the past few decades, investigation of human epigenetic modification has focused on DNA and proteins, with analysis of chromatin remodeling, gene silencing, DNA methylation, and histone modification. In comparison, RNA-related modification has received less attention, although in recent years, with the continuous development of detection technology, hundreds of different RNA modifications have been discovered, among which N6-methyladenosine (m6A) RNA methylation is the most abundant.1Yue Y. Liu J. He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation.Genes Dev. 2015; 29: 1343-1355Crossref PubMed Scopus (381) Google Scholar m6A in RNA is an epigenetic modification in which a hydrogen atom (–H) connected to the sixth nitrogen atom (N6) on adenine is replaced by a methyl group (–CH3) (Figure S1). With the advent of high-throughput sequencing technology, many m6A RNA methylation sites have been discovered, which are mainly concentrated in exons and 3′ untranslated regions (UTRs), with the highest concentration near the termination codon. Each transcript contains three to five or more m6A modification sites, accounting for 0.1%–0.4% of total adenine (m6A/A).2Rottman F. Shatkin A.J. Perry R.P. Sequences containing methylated nucleotides at the 5′ termini of messenger RNAs: possible implications for processing.Cell. 1974; 3: 197-199Abstract Full Text PDF PubMed Scopus (165) Google Scholar In eukaryotic RNAs, m6A mostly occurs in the critically conserved motif RRACH (R = G, A, and U; H = U, A, and C) (Figure 1),3Csepany T. Lin A. Baldick Jr., C.J. Beemon K. Sequence specificity of mRNA N6-adenosine methyltransferase.J. Biol. Chem. 1990; 265: 20117-20122Abstract Full Text PDF PubMed Google Scholar,4Zhang C. Chen Y. Sun B. Wang L. Yang Y. Ma D. Lv J. Heng J. Ding Y. Xue Y. et al.m6A modulates haematopoietic stem and progenitor cell specification.Nature. 2017; 549: 273-276Crossref PubMed Scopus (208) Google Scholar and it is most common in mRNA but is also widely found in long non-coding RNA (lncRNA), tRNA, rRNA, and microRNA (miRNA). A large number of studies have confirmed that m6A RNA mainly interacts with three types of proteins, namely methyltransferases, demethylases, and reader proteins. Similar to DNA methylation, RNA methylation is also dynamic and reversible, and the related reactions are mainly catalyzed by methyltransferases and demethylases; methyltransferases catalyze the installation of m6A on RNA, while the demethylases remove m6A modifications (Figure 1). The biological function of dynamic RNA methylation is mainly mediated by reader proteins, which act by recognizing and binding to m6A and reading the biological information, mainly for splicing processing, nucleus to cytoplasm transport, and stabilization, translation, and degradation of RNA (Figure 2). Members of the YT521-B homology (YTH) domain family have been identified as m6A readers, including YTH domain family protein 1 (YTHDF1), YTH domain family protein 2 (YTHDF2), YTH domain family protein 3 (YTHDF3), YTH domain containing 1 (YTHDC1), and YTH domain containing 2 (YTHDC2), and they have conserved m6A-binding domains that can bind to the RNA m6A site. In addition, the heterogeneous nuclear ribonucleoprotein (HnRNP) family, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs), and eIF3 can be combined with the m6A site and function as readers. According to relevant reports, YTHDF1,5Wang X. Zhao B.S. Roundtree I.A. Lu Z. Han D. Ma H. Weng X. Chen K. Shi H. He C. N6-methyladenosine modulates messenger RNA translation efficiency.Cell. 2015; 161: 1388-1399Abstract Full Text Full Text PDF PubMed Scopus (1103) Google Scholar YTHDC2,6Hsu P.J. Zhu Y. Ma H. Guo Y. Shi X. Liu Y. Qi M. Lu Z. Shi H. Wang J. et al.Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis.Cell Res. 2017; 27: 1115-1127Crossref PubMed Scopus (281) Google Scholar and eIF37Lin S. Choe J. Du P. Triboulet R. Gregory R.I. The m6A methyltransferase METTL3 promotes translation in human cancer cells.Mol. Cell. 2016; 62: 335-345Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar have been shown to promote target mRNA translation, and YTHDF2 participates in RNA degradation,8Wang 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 (1454) Google Scholar while YTHDF3 plays a synergistic role, interacting with YTHDF1 to promote RNA translation, and binding with YTHDF2 to promote RNA degradation.9Shi H. Wang X. Lu Z. Zhao B.S. Ma H. Hsu P.J. Liu C. He C. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA.Cell Res. 2017; 27: 315-328Crossref PubMed Scopus (500) Google Scholar YTHDC1 facilitates RNA splicing and output,10Roundtree I.A. Luo G.Z. Zhang Z. Wang X. Zhou T. Cui Y. Sha J. Huang X. Guerrero L. Xie P. et al.YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs.eLife. 2017; 6: e31311Crossref PubMed Scopus (304) Google Scholar and HnRNP is involved in the splicing of RNA.11Liu N. Dai Q. Zheng G. He C. Parisien M. Pan T. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.Nature. 2015; 518: 560-564Crossref PubMed Scopus (768) Google Scholar IGF2BPs enhances the expression of target mRNA by promoting its stability.12Huang 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 N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.Nat. Cell Biol. 2018; 20: 285-295Crossref PubMed Scopus (513) Google Scholar As the writers of m6A RNA methylation, methyltransferases and their components can regulate a variety of cellular physiological processes, including cell cycle, cell growth, cell differentiation, and apoptosis. In addition, methyltransferase components are involved in phenotypic transformation of Drosophila13Guo J. Tang H.W. Li J. Perrimon N. Yan D. Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex.Proc. Natl. Acad. Sci. USA. 2018; 115: 3674-3679Crossref PubMed Scopus (52) Google Scholar and embryonic development of mice.14Mendel M. Chen K.M. Homolka D. Gos P. Pandey R.R. McCarthy A.A. Pillai R.S. Methylation of Structured RNA by the m6A writer METTL16 is essential for mouse embryonic development.Mol. Cell. 2018; 71: 986-1000.e11Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Furthermore, the relationship between methyltransferases and cancers has become an intense area of investigation. Herein, we review the key roles of methyltransferases in human cancers and their mechanisms of tumorigenesis. In the 1990s, Bokar et al.15Bokar J.A. Shambaugh M.E. Polayes D. Matera A.G. Rottman F.M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.RNA. 1997; 3: 1233-1247PubMed Google Scholar isolated 200-kDa (MT-A) and 800-kDa (MT-B) nuclear subcomplexes from HeLa cells and identified an m6A methyltransferase multi-component complex. This complex utilizes S-adenosylmethionine (SAM) as a methyl donor to provide a methyl group that replaces the hydrogen atom of the sixth nitrogen center of adenine.15Bokar J.A. Shambaugh M.E. Polayes D. Matera A.G. Rottman F.M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.RNA. 1997; 3: 1233-1247PubMed Google Scholar,16Narayan P. Rottman F.M. An in vitro system for accurate methylation of internal adenosine residues in messenger RNA.Science. 1988; 242: 1159-1162Crossref PubMed Scopus (92) Google Scholar Subsequently, a 70-kDa protein, MT-A70, was extracted from the MT-A complex and was named methyltransferase-like 3 (METTL3).17Tuck M.T. Partial purification of a 6-methyladenine mRNA methyltransferase which modifies internal adenine residues.Biochem. J. 1992; 288: 233-240Crossref PubMed Scopus (27) Google Scholar Further investigation led to the discovery of important methyltransferase components, such as methyltransferase-like 14 (METTLl4), Wilms tumor 1-associated protein (WTAP), protein virilizer homolog (VIRMA), E3 ubiquitin-protein ligase Hakai (HAKAI), zinc finger CCCH domain-containing protein 13 (ZC3H13), RNA-binding protein 15 (RBM15), and methyltransferase-like 16 (METTL16) (Table 1; Table S1). These discoveries have greatly advanced our understanding of m6A RNA methylation.Table 1Multiple functions exerted by m6A RNA methyltransferases in various cancersMoleculeRoleCancerTargetMechanismReferencesMETTL3oncogenelung cancermRNAMETTL3-eIF3 cycle promotes translation of oncogenes18Choe J. Lin S. Zhang W. Liu Q. Wang L. Ramirez-Moya J. Du P. Kim W. Tang S. 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Yang Y. et al.m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.Nat. Cell Biol. 2018; 20: 1074-1083Crossref PubMed Scopus (248) Google ScholarMETTL14oncogeneAMLmRNAinhibits myeloid differentiation of AMLs31Weng H. Huang H. Wu H. Qin X. Zhao B.S. 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. 2018; 22: 191-205.e9Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholaroncogenepancreatic cancermRNAactivates the signaling pathway32Kong F. Liu X. Zhou Y. Hou X. He J. Li Q. Miao X. Yang L. Downregulation of METTL14 increases apoptosis and autophagy induced by cisplatin in pancreatic cancer cells.Int. J. Biochem. Cell Biol. 2020; 122: 105731Crossref PubMed Scopus (12) Google ScholarsuppressorRCCmRNAinhibits the expression of the oncogene P2RX633Gong D. Zhang J. Chen Y. Xu Y. Ma J. Hu G. Huang Y. Zheng J. Zhai W. Xue W. The m6A-suppressed P2RX6 activation promotes renal cancer cells migration and invasion through ATP-induced Ca2+ influx modulating ERK1/2 phosphorylation and MMP9 signaling pathway.J. Exp. Clin. Cancer Res. 2019; 38: 233Crossref PubMed Scopus (42) Google Scholaroncogenebreast cancermiRNApromotes the maturation of oncogenic miRNA34Yi D. Wang R. Shi X. Xu L. Yilihamu Y. Sang J. METTL14 promotes the migration and invasion of breast cancer cells by modulating N6-methyladenosine and hsa-miR-146a-5p expression.Oncol. Rep. 2020; 43: 1375-1386PubMed Google ScholarsuppressorHCCmiRNApromotes the maturation of cancer suppressor miRNA35Ma J.Z. Yang F. Zhou C.C. Liu F. Yuan J.H. Wang F. Wang T.T. Xu Q.G. Zhou W.P. Sun S.H. 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Accumulating evidence shows that METTL3 can participate in the development of cancer through various mechanisms. For example, METTL3 regulates the level and stability of target gene mRNA by regulating the homeostasis of m6A, thereby promoting transcript translation and protein synthesis. METTL3 and METTL14 form stable complexes at a 1:1 ratio.51Wang P. Doxtader K.A. Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases.Mol. Cell. 2016; 63: 306-317Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar In vitro, the combination of the two can significantly improve methylation efficiency. In vivo, METTL14 recognizes RNA substrates and serves as an RNA-binding platform, and METTL3 has the main methyltransferase catalytic domain. The METTL3-METTL14 complex is also the only known m6A methyltransferase heterodimer complex (Figure 1).52Ruszkowska A. Ruszkowski M. Dauter Z. Brown J.A. Structural insights into the RNA methyltransferase domain of METTL16.Sci. Rep. 2018; 8: 5311Crossref PubMed Scopus (48) Google Scholar Furthermore, METTL3 can recruit the translation initiation factor, eIF3, to the translation initiation complex when combined with certain mRNAs to enhance translation,7Lin S. Choe J. Du P. Triboulet R. Gregory R.I. The m6A methyltransferase METTL3 promotes translation in human cancer cells.Mol. Cell. 2016; 62: 335-345Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar for example, with epidermal growth factor receptor (EGFR) and bromodomain-containing protein 4 (BRD4).18Choe J. Lin S. Zhang W. Liu Q. Wang L. Ramirez-Moya J. Du P. Kim W. Tang S. Sliz P. et al.mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.Nature. 2018; 561: 556-560Crossref PubMed Scopus (189) Google Scholar In addition, METTL3 is also a chromatin-based regulatory factor necessary for leukemia status.19Barbieri I. Tzelepis K. Pandolfini L. Shi J. Millán-Zambrano G. Robson S.C. Aspris D. Migliori V. Bannister A.J. Han N. et al.Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.Nature. 2017; 552: 126-131Crossref PubMed Scopus (363) Google Scholar It locates to the transcription initiation point of SP1 and SP2, induces m6A modification of the relevant mRNA coding region, and enhances its translation by alleviating ribosomal stasis. In breast cancer,20Cai X. Wang X. Cao C. Gao Y. Zhang S. Yang Z. Liu Y. Zhang X. Zhang W. Ye L. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g.Cancer Lett. 2018; 415: 11-19Crossref PubMed Scopus (185) Google Scholar METTL3 promotes the expression of an oncoprotein, HBXIP, in an m6A-dependent manner. HBXIP inhibits the tumor suppressor miRNA let-7g, and because let-7g inhibits METTL3, the positive feedback pathway, HBXIP-let-7g-METTL3-HBXIP, promotes the progression of breast cancer. Similarly, METTL3 upregulates RAB2B expression to promote the growth of cervical cancer cells.53Hu Y. Li Y. Huang Y. Jin Z. Wang C. Wang H. Xu J. METTL3 regulates the malignancy of cervical cancer via post-transcriptional regulation of RAB2B.Eur. J. Pharmacol. 2020; 879: 173134Crossref PubMed Scopus (7) Google Scholar In bladder cancer, METTL3 upregulates the expression of the adhesion molecule, ITGA6, to enhance the adhesion, migration, and invasion of tumor cells and to mediate signal output.54Jin H. Ying X. Que B. Wang X. Chao Y. Zhang H. Yuan Z. Qi D. Lin S. Min W. et al.N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer.EBioMedicine. 2019; 47: 195-207Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar METTL3 also promotes bladder cancer progression by regulating the AFF4-nuclear factor κB (NF-κB)-MYC multi-level signal network,55Cheng M. Sheng L. Gao Q. Xiong Q. Zhang H. Wu M. Liang Y. Zhu F. Zhang Y. Zhang X. et al.The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network.Oncogene. 2019; 38: 3667-3680Crossref PubMed Scopus (131) Google Scholar and the METTL3-m6A-CDCP1 axis promotes the growth of chemically transformed cells and bladder cancer cells.56Yang F. Jin H. Que B. Chao Y. Zhang H. Ying X. Zhou Z. Yuan Z. Su J. Wu B. et al.Dynamic m6A mRNA methylation reveals the role of METTL3-m6A-CDCP1 signaling axis in chemical carcinogenesis.Oncogene. 2019; 38: 4755-4772Crossref PubMed Scopus (64) Google Scholar In prostate carcinoma, researchers revealed a METTL3-m6A-MYC axis.57Yuan Y. Du Y. Wang L. Liu X. The M6A methyltransferase METTL3 promotes the development and progression of prostate carcinoma via mediating MYC methylation.J. Cancer. 2020; 11: 3588-3595Crossref PubMed Scopus (17) Google Scholar METTL3 enhances MYC expression and plays a carcinogenic role by increasing the level of m6A in the MYC transcript. In colorectal carcinoma (CRC),58Li T. Hu P.S. Zuo Z. Lin J.F. Li X. Wu Q.N. Chen Z.H. Zeng Z.L. Wang F. Zheng J. et al.METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma.Mol. Cancer. 2019; 18: 112Crossref PubMed Scopus (163) Google Scholar,59Zhu W. Si Y. Xu J. Lin Y. Wang J.Z. Cao M. Sun S. Ding Q. Zhu L. Wei J.F. Methyltransferase like 3 promotes colorectal cancer proliferation by stabilizing CCNE1 mRNA in an m6A-dependent manner.J. Cell. Mol. Med. 2020; 24: 3521-3533Crossref PubMed Scopus (25) Google Scholar SOX2 and CCNE1 are downstream target genes of METTL3. As an oncogene, METTL3 maintains the expression of SOX2 and CCNE1 in CRCs through an m6A-dependent mechanism, maintains the stemness of CRCs, and promotes proliferation and metastasis. Furthermore, in CRC with high glucose metabolism,21Shen 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. 2020; 19: 72Crossref PubMed Scopus (47) Google Scholar METTL3 induces CRC in a glycolysis-dependent manner. Mechanistically, METTL3 directly interacts with the mRNA of the glycolysis-related genes HK2 and GLUT1, thereby activating glycolysis in tumor cells. In gastric cancer22Wang Q. Chen C. Ding Q. Zhao Y. Wang Z. Chen J. Jiang Z. Zhang Y. Xu G. 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