N6-Methyladenosine: A Potential Breakthrough for Human Cancer
2019; Cell Press; Volume: 19; Linguagem: Inglês
10.1016/j.omtn.2019.12.013
ISSN2162-2531
AutoresLina Liu, Yuwei Wang, Jie Wu, Jingwen Liu, Zongchang Qin, Hong Fan,
Tópico(s)Cancer-related molecular mechanisms research
ResumoAmong more than 100 types of identified RNA modification, N6-methyladenosine (m6A) modification is the predominant mRNA modification, which regulates RNA splicing, translocation, stability, and translation. m6A modification plays critical roles in the growth, differentiation, and metabolism of cells. As a dynamic and reversible modification, m6A is catalyzed by "writers" (RNA methyltransferases), removed by "erasers" (demethylases), and interacts with "readers" (m6A-binding proteins). With more advanced technology applied to research, the molecular mechanisms of RNA methyltransferase, demethylase, and m6A-binding protein have been revealed. An increasing number of studies have implicated the correlation between m6A modification and human cancers. In this review, we summarize that the occurrence and development of various human cancers are associated with aberrant m6A modification. We also discuss the progress in research related to m6A modification, providing novel therapeutic insight and potential breakthrough in anticancer therapy. Among more than 100 types of identified RNA modification, N6-methyladenosine (m6A) modification is the predominant mRNA modification, which regulates RNA splicing, translocation, stability, and translation. m6A modification plays critical roles in the growth, differentiation, and metabolism of cells. As a dynamic and reversible modification, m6A is catalyzed by "writers" (RNA methyltransferases), removed by "erasers" (demethylases), and interacts with "readers" (m6A-binding proteins). With more advanced technology applied to research, the molecular mechanisms of RNA methyltransferase, demethylase, and m6A-binding protein have been revealed. An increasing number of studies have implicated the correlation between m6A modification and human cancers. In this review, we summarize that the occurrence and development of various human cancers are associated with aberrant m6A modification. We also discuss the progress in research related to m6A modification, providing novel therapeutic insight and potential breakthrough in anticancer therapy. N6-adenosine is the most prevalent epigenetic modification in RNA, originally identified in mRNAs in the 1970s.1Desrosiers R. Friderici K. Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.Proc. Natl. Acad. Sci. USA. 1974; 71: 3971-3975Crossref PubMed Scopus (616) Google Scholar Similar to the methylation of DNA, N6-methyladenosine (m6A) methylation regulates post-transcriptional expression without changing the base sequence. m6A is the most abundant internal RNA modification, enriched at the RRACH motif in 3′ UTRs, 5′ UTRs, and near stop codons.2Roundtree I.A. Evans M.E. Pan T. He C. 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Pharmacother. 2019; 112: 108613Crossref PubMed Scopus (5) Google Scholar It modulates RNA processing and metabolism, including alternative splicing, transport, translation, and degradation.7Lan Q. Liu P.Y. Haase J. Bell J.L. Hüttelmaier S. Liu T. The critical role of RNA m6A methylation in cancer.Cancer Res. 2019; 79: 1285-1292Crossref PubMed Scopus (48) Google Scholar As a dynamic and reversible modification, m6A deposition is regulated by methylases and demethylases. m6A-binding proteins subsequently recognize and bind the m6A-rich domain, inducing decay or accelerating translation efficiency. With the advancement of methods for detecting m6A and proteins, many enzymes have been identified and the functions and mechanisms of them have gradually emerged. Some studies looking into the mechanism of alternative splicing regulation have uncovered the function of m6A. m6A near splice sites in nascent pre-mRNA mediates heterogeneous nuclear ribonucleoprotein G (hnRNPG) binding. hnRNPG interacts with RNA polymerase II (RNAPII) with Arg-Gly-Gly (RGG) motifs, thereby modulating RNAPII occupancy and alternative splicing.8Zhou K.I. Shi H. Lyu R. Wylder A.C. Matuszek Ż. Pan J.N. He C. Parisien M. Pan T. Regulation of co-transcriptional pre-mRNA splicing by m6A through the low-complexity protein hnRNPG.Mol. Cell. 2019; 76: 70-81.e9Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Moreover, the location of m6A on nascent RNA is likely to modulate splicing kinetics. m6A co-transcriptionally depositing near splice junctions promotes fast splicing, while m6A in introns indicates long, slowly processed introns and alternative splicing events.9Louloupi A. Ntini E. Conrad T. Ørom U.A.V. Transient N-6-methyladenosine transcriptome sequencing reveals a regulatory role of m6A in splicing efficiency.Cell Rep. 2018; 23: 3429-3437Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar m6A was also found in precursor mRNA (pre-mRNA), tRNA, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) later, but the functions of m6A in circular RNA (circRNA) remain elusive.10Alarcón C.R. Lee H. Goodarzi H. Halberg N. Tavazoie S.F. N6-methyladenosine marks primary microRNAs for processing.Nature. 2015; 519: 482-485Crossref PubMed Scopus (442) Google Scholar, 11Patil D.P. Chen C.K. Pickering B.F. Chow A. Jackson C. Guttman M. Jaffrey S.R. m6A RNA methylation promotes XIST-mediated transcriptional repression.Nature. 2016; 537: 369-373Crossref PubMed Scopus (327) Google Scholar, 12Chen X.Y. Zhang J. Zhu J.S. The role of m6A RNA methylation in human cancer.Mol. Cancer. 2019; 18: 103Crossref PubMed Scopus (38) Google Scholar, 13Warda A.S. Kretschmer J. Hackert P. Lenz C. Urlaub H. Höbartner C. Sloan K.E. Bohnsack M.T. Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs.EMBO Rep. 2017; 18: 2004-2014Crossref PubMed Scopus (99) Google Scholar, 14Lence T. Paolantoni C. Worpenberg L. Roignant J.Y. Mechanistic insights into m6A RNA enzymes.Biochim. Biophys. Acta. Gene Regul. Mech. 2019; 1862: 222-229Crossref PubMed Scopus (8) Google Scholar. m6A in circRNAs are frequently derived from exons that are not methylated in mRNAs, and a single m6A modification is enough to initiate circRNA translation, although the "writers" and "readers" are the same as those that participate in m6A modification in mRNA.15Das A. Gorospe M. Panda A.C. The coding potential of circRNAs.Aging (Albany N.Y.). 2018; 10: 2228-2229PubMed Google Scholar,16Zhou C. Molinie B. Daneshvar K. Pondick J.V. Wang J. Van Wittenberghe N. Xing Y. Giallourakis C.C. Mullen A.C. Genome-wide maps of m6A circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs.Cell Rep. 2017; 20: 2262-2276Abstract Full Text Full Text PDF PubMed Google Scholar With specific m6A-related mechanism, circRNA is involved in tumorigenesis, which indicates the important role of circRNA in human cancer.17Zhao W. Cui Y. Liu L. Qi X. Liu J. Ma S. Hu X. Zhang Z. Wang Y. Li H. et al.Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop.Cell Death Differ. 2019; (Published online September 30, 2019)https://doi.org/10.1038/s41418-019-0423-5Crossref Scopus (16) Google Scholar With burgeoning medical technology, substantial progress has been made in the detection and diagnosis of cancer. Accumulating studies indicate that aberrant m6A levels closely correlate with carcinogenesis and the progression and metastasis of cancer cells. The dysregulation of writers, "erasers," and readers is proved to be the culprit, activating oncogenes or inhibiting tumor suppressor genes by activating signaling pathways.18Tuncel G. Kalkan R. Importance of m N6-methyladenosine (m6A) RNA modification in cancer.Med. Oncol. 2019; 36: 36Crossref PubMed Scopus (5) Google Scholar,19Chen B. Li Y. Song R. Xue C. Xu F. Functions of RNA N6-methyladenosine modification in cancer progression.Mol. Biol. Rep. 2019; 46: 2567-2575Crossref PubMed Scopus (4) Google Scholar Potential therapeutic targets have also been offered by researching the mechanisms of carcinogenesis. In this review, we discuss the relationships between human cancers and new discoveries in the regulation of m6A modification. m6A writers (methyltransferases) can install the m6A RNA modification (Figure 1). METTL3 is the first known RNA m6A methyltransferase. Then, METTL14 was identified, forming a stable METTL3-METTL14 complex that is also called the m6A-METTL complex (MAC).20Liu J. Yue Y. Han D. Wang X. Fu Y. Zhang L. Jia G. Yu M. Lu Z. Deng X. et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.Nat. Chem. Biol. 2014; 10: 93-95Crossref PubMed Scopus (712) Google Scholar The interface of the heterodimer is formed by strands β4–5 and helix α4 of each methyltransferase domain (MTD), and it contains hydrogen bonds as well as hydrophobic interactions. The hydrophobic region centering on strands β4–5 is protected from solvent exposure by an N-terminal extension of METTL14. In addition, METTL3 and METTL14 each forms a partially disordered loop that can insert an aromatic residue into a hydrophobic pocket in the other subunit. All of these unique structural features enhance the stability and compactness of MAC.14Lence T. Paolantoni C. Worpenberg L. Roignant J.Y. Mechanistic insights into m6A RNA enzymes.Biochim. Biophys. Acta. Gene Regul. Mech. 2019; 1862: 222-229Crossref PubMed Scopus (8) Google Scholar,21Śledź P. Jinek M. Structural insights into the molecular mechanism of the m6A writer complex.eLife. 2016; 5: e18434Crossref PubMed Google Scholar METTL3 is the only catalytic subunit of MAC, while METTL14 maintains MAC integrity and is likely to mediate RNA binding. Sequence analysis indicated that the METTL3 catalytic site contains a more conserved DPPW motif, whereas the catalytic motif of METTL14 is a divergent EPPL sequence. Moreover, two Cys-Cys-Cys-His (CCCH)-type zinc fingers of METTL3, adjacent to MTD3 and connected by an anti-parallel β sheet, are also necessary for methylation activity. The zinc finger domain (ZFD) specifically recognizes the 5′-GGACU-3′ consensus sequence of RNA, forming an RNA-binding interface. Although METTL14 has the folding configuration similar to METTL13, the cavity where RNA substrates bind is not possessed.22Wang 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 (201) Google Scholar,23Huang J. Dong X. Gong Z. Qin L.Y. Yang S. Zhu Y.L. Wang X. Zhang D. Zou T. Yin P. Tang C. Solution structure of the RNA recognition domain of METTL3-METTL14 N6-methyladenosine methyltransferase.Protein Cell. 2019; 10: 272-284Crossref PubMed Scopus (15) Google Scholar However, recent research has uncovered the important role of METTL14 in the crosstalk between histone modification and RNA methylation. METTL14 recognizes and directly binds with histone H3 trimethylation at Lys36 (H3K36me3), facilitating MAC to adjacent RNAPII, thereby installing m6A in actively transcribed nascent RNAs co-transcriptionally. This mechanism may suggest how m6A is specifically deposited in the transcriptome.24Huang H. Weng H. Zhou K. Wu T. Zhao B.S. Sun M. Chen Z. Deng X. Xiao G. Auer F. et al.Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally.Nature. 2019; 567: 414-419Crossref PubMed Scopus (41) Google Scholar m6A is catalyzed by writers and removed by erasers (FTO and ALKBH5). MACOM, consisting of WTAP, VIRMA, Hakai, RBM15, and ZC3H13, ensures the location of the METTL3-METTL14 core complex to nuclear speckle. m6A modification exerts biological functions by binding to YTHDC1–2, YTHDF1–3, HNRNPA2B1, IGF2BP1–3, eIF3, and eIF4A3. In the nucleus, YTHDC1 and HNRNPA2B1 bind m6A and perform multiple functions. In the cytoplasm, YTHDC2, YTHDF1–3, IGF2BP1–3, eIF3, and eIF4A3 induce translation or degradation of transcripts. eIF3 can promote translation by directly binding m6A in the 5′ UTR. The discovery of Wilms' tumor 1-associating protein (WTAP) enriched the composition of the m6A methyltransferase complex. WTAP exhibits affinity for the methyltransferase complex, locating the METTL3-METTL14 complex at nuclear speckles and recruiting them to mRNA targets, regulating expression and alternative splicing of genes with the assistance of METTL3.25Ping X.L. Sun B.F. Wang L. Xiao W. Yang X. Wang W.J. Adhikari S. Shi Y. Lv Y. Chen Y.S. et al.Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.Cell Res. 2014; 24: 177-189Crossref PubMed Scopus (518) Google Scholar Studies focusing on interaction surfaces within the METTL3-METTL14-WTAP complex unveiled the novel overall architecture. In WTAP, the METTL3-binding surface is within the N-terminal 150 aa, while the WTAP interaction surface on METTL3 is an N-terminal helical structure that is necessary and sufficient for WTAP-METTL3 interaction. Strikingly, METTL3 phosphorylation in the WTAP interaction surface does not affect subcellular localization, WTAP interaction, or catalytic activity. Moreover, the C-terminal arginine-glycine repeats (RGG) of METTL14, contributing to RNA substrate binding, are indispensable for MAC catalytic activity. The finding is consistent with previous conclusions about the function of METTL14.26Schöller E. Weichmann F. Treiber T. Ringle S. Treiber N. Flatley A. Feederle R. Bruckmann A. Meister G. Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex.RNA. 2018; 24: 499-512Crossref PubMed Scopus (53) Google Scholar More WTAP-related proteins and their relevant regulatory factors have been discovered in further studies. Hitherto, we defined the complex consisting of WTAP, VIRMA, Hakai, RBM15 (RNA-binding motif protein 15), and ZC3H13 (a zinc-finger protein) as MACOM (m6A-METTL-associated complex).11Patil D.P. Chen C.K. Pickering B.F. Chow A. Jackson C. 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METTL16 participates in splicing regulation by catalyzing N6-methylation in A43, which is in the specific sequence of U6 small nuclear RNA (snRNA). The alteration in A43 can influence the base pairing at 5′ splice sites of pre-mRNAs during splicing.13Warda A.S. Kretschmer J. Hackert P. Lenz C. Urlaub H. Höbartner C. Sloan K.E. Bohnsack M.T. Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs.EMBO Rep. 2017; 18: 2004-2014Crossref PubMed Scopus (99) Google Scholar Intriguingly, studies also revealed METTL16 as a regulator that maintains SAM homeostasis by binding with MAT2A mRNA hairpins, implicating its likely important role in early development.31Doxtader K.A. Wang P. Scarborough A.M. Seo D. Conrad N.K. Nam Y. Structural basis for regulation of METTL16, an S-adenosylmethionine homeostasis factor.Mol. Cell. 2018; 71: 1001-1011.e4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,32Shima H. Matsumoto M. 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The dynamics of FTO binding and demethylation from the m6A motifs.RNA Biol. 2019; 16: 1179-1189Crossref PubMed Scopus (1) Google Scholar Additionally, FTO also mediates the demethylation of cap N6, 2′-O-dimethyladenosine (cap m6Am) in snRNA and mRNA. Compared with the demethylation of m6A, FTO act differently in m6Am demethylation, which can be accounted for by different cellular distribution features of FTO. Experiments conducted in polyadenylated RNAs among different cell lines manifested that FTO is more active with regard to m6Am (81.9% of m6Am and 20.3% of m6A were demethylated in vitro). m6A is preferentially demethylated by FTO in nucleus, whereas cap m6Am is a prominent target in cytoplasm.36Wei J. Liu F. Lu Z. Fei Q. Ai Y. He P.C. Shi H. Cui X. Su R. Klungland A. et al.Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm.Mol. Cell. 2018; 71: 973-985.e5Abstract Full Text Full Text PDF PubMed Google Scholar The cap m6Am at +1 position from 5′ cap in mRNA confers resistance to mRNA-decapping enzyme DCP2 on transcripts, thereby enhancing mRNA stability.37Mauer J. Luo X. Blanjoie A. Jiao X. Grozhik A.V. Patil D.P. Linder B. Pickering B.F. Vasseur J.J. Chen Q. et al.Reversible methylation of m6Am in the 5′ cap controls mRNA stability.Nature. 2017; 541: 371-375Crossref PubMed Scopus (281) Google Scholar FTO-mediated m6Am demethylation was also detected in snRNAs (U1 RNA and U2 RNA; both the cap and internal m6Am modifications are more significant in U2 RNA), but m6A demethylation only happened in U6 RNA.36Wei J. Liu F. Lu Z. Fei Q. Ai Y. He P.C. Shi H. Cui X. Su R. Klungland A. et al.Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm.Mol. 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N6-methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5.Sci. Rep. 2016; 6: 25677Crossref PubMed Google Scholar m6A modification exerts biological functions by binding to YTH domain-containing proteins (YTHDC1–2), YTH-family proteins (YTHDF1–3), and other interacting factors. The proteins are collectively defined as readers. In the nucleus, YTHDC1 promotes exon inclusion of targeted mRNAs and regulates mRNA splicing and export from nucleus to cytoplasm by recruiting pre-mRNA splicing factor SFSF3.41Wang 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 (688) Google Scholar,42Roundtree I.A. Luo G.Z. Zhang Z. Wang X. Zhou T. Cui Y. Sha J. Huang X. Guerrero L. 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In such an m6A-dependent manner, IGF2BP1/2/3 prevent target mRNAs from degradation and promote mRNA translation.48Huang 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 (211) Google Scholar AML is a malignant disease originating from hematopoietic stem cells or progenitor cells. Chemotherapy and hematopoietic stem cell transplantation are general treatments for AML, but targeted therapy, demethylation therapy, and immunotherapy also show promising therapeutic effects. With high expression of methyltransferases, AML cells feature elevated m6A, which contributes to the maintenance of multilineage differentiation potential and inhibits cell differentiation in AML.49Vu L.P. Pickering B.F. Cheng Y. Zaccara S. Nguyen D. Minuesa G. Chou T. Chow A. Saletore Y. MacKay M. et al.The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.Nat. Med. 2017; 23: 1369-1376Crossref PubMed Scopus (0) Google Scholar,50Barbieri 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 (196) Google Scholar METTL3 recruited by CEBPZ promotes translation of SP1 by upregulating the m6A level. SP1 subsequently activates the oncogene c-MYC, which can result in the development of AML.50Barbieri I. Tzelepis K. Pandolfini L. Shi J. Millán-Zambrano G. Robson S.C. Aspris D. Migliori V. Bannister A.J. 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