m6A RNA甲基化在肿瘤发生发展中的作用

doi:10.13560/j.cnki.biotech.bull.1985.2018-1082

摘要/Abstract

摘要： m6A 甲基化是于1974年首次被发现的一种RNA分子上的甲基化修饰,近年来已成为生命科学领域的研究热点。m6A修饰在哺乳动物细胞中是动态可逆的,是类似于DNA和组蛋白修饰的另一种表观遗传调控。这种RNA化学标记是由m6A“Writers”的蛋白质产生,可以被m6A“Erasers”（即去甲基酶）逆转。此外,“Readers”可以识别含m6A的mRNA,并相应地调节下游基因的表达。m6A RNA甲基化参与了RNA生命周期的各个阶段,从RNA加工、核输出、翻译调控到RNA降解,表明m6A具有影响RNA代谢相关多方面的功能。最近的研究表明,在不同的组织、细胞系和时空模型中,m6A的修饰是一个复杂的调控网络,m6A甲基化与肿瘤的发生和发展密切相关。主要围绕m6A的分子调控机制、生理意义及其在几种人类肿瘤中的研究进展进行综述,旨在为癌症的早期临床诊断和靶向治疗提供新的思路。

关键词: RNA甲基化, m6A甲基化, 肿瘤

Abstract: m6A methylation,which was first discovered in 1974,is a kind of methylation modification on RNA molecule. In recent years,it has become a research hotspot in life science. Modifications of m6A are dynamic and reversible in mammalian cells,which have been proposed as another type of epigenetic regulation similar to DNA and histone modifications. This RNA chemical marker is produced by the protein of m6A“Writers”and can be reversed by m6A“Erasers”（demethylase）. In addition,“Readers”can recognize the mRNA of m6A,and accordingly regulate the expression of downstream genes. m6A RNA methylation is involved in all stages in the life cycle of RNA,from RNA processing,nuclear export,translation modulation to RNA degradation,which suggests its potential of influencing a plurality of aspects of RNA metabolism. All of the recent studies reveal that m6A modification is a complicated regulation network in different tissues,cell lines,and space-time models,and it is be closely associated with tumor initiation and progression. This review focuses on the molecular regulatory mechanism of m6A,its physiological significance and the research progress in several kinds of human tumors,aiming at providing new insight for early clinical diagnosis and targeted therapy of cancer.

Key words: RNA methylation, m6A methylation, tumor

龙文林, 郭辉, 盛杰, 宋如晦, 徐瑶. m6A RNA甲基化在肿瘤发生发展中的作用[J]. 生物技术通报, 2019, 35(6): 178-186.

LONG Wen-lin, GUO Hui, SHENG Jie, SONG Ru-hui, XU Yao. Role of m6A RNA Methylation in Tumorigenesis and Development[J]. Biotechnology Bulletin, 2019, 35(6): 178-186.

参考文献

[1] Dubin DT, Taylor RH.The methylation state of poly A-containing messenger RNA from cultured hamster cells[J]. Nucleic Acids Res, 1975, 2:1653-1668.
[2] Boccaletto P, Machnicka MA, Purta E, et al.MODOMICS:a database of RNA modification pathways. 2017 update[J]. Nucleic Acids Res, 2018, 46:D303-d307.
[3] Desrosiers R, Friderici K, Rottman F.Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells[J]. Proc Natl Acad USA, 1974, 71:3971-3975.
[4] Wei CM, Gershowitz A, Moss B.Methylated nucleotides block 5’ terminus of HeLa cell messenger RNA[J]. Cell, 1975, 4:379-386.
[5] Krug RM, Morgan MA, Shatkin AJ.Influenza viral mRNA contains internal N6-methyladenosine and 5’-terminal 7-methylguanosine in cap structures[J]. J Virol, 1976, 20:45-53.
[6] Sommer S, Salditt-Georgieff M, Bachenheimer S, et al.The methylation of adenovirus-specific nuclear and cytoplasmic RNA[J]. Nucleic Acids Res, 1976, 3:749-765.
[7] Kennedy TD, Lane BG.Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5’-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos[J]. Can J Biochem, 1979, 57:927-931.
[8] Deng X, Chen K, Luo GZ, et al.Widespread occurrence of N6-methyladenosine in bacterial mRNA[J]. Nucleic Acids Res, 2015, 43:6557-6567.
[9] Narayan P, Rottman FM.An in vitro system for accurate methylation of internal adenosine residues in messenger RNA[J]. Science, 1988, 242:1159-1162.
[10] Narayan P, Ludwiczak RL, Goodwin EC, et al.Context effects on N6-adenosine methylation sites in prolactin mRNA[J]. Nucleic Acids Res, 1994, 22:419-426.
[11] Csepany T, Lin A, Baldick CJ, Jr. , et al. Sequence specificity of mRNA N6-adenosine methyltransferase[J]. J Biol Chem, 1990, 265:20117-20122.
[12] Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al.Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J]. Nature, 2012, 485:201-206.
[13] Meyer KD, Saletore Y, Zumbo P, et al.Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons[J]. Cell, 2012, 149:1635-1646.
[14] Bodi Z, Bottley A, Archer N, et al.Yeast m6A methylated mRNAs are enriched on translating ribosomes during meiosis, and under rapamycin treatment[J]. PLoS One, 2015, 10:e0132090.
[15] Stoltzfus CM, Dane RW.Accumulation of spliced avian retrovirus mRNA is inhibited in S-adenosylmethionine-depleted chicken embryo fibroblasts[J]. J Virol, 1982, 42:918-931.
[16] Carroll SM, Narayan P, Rottman FM.N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA[J]. Mol Cell Biol, 1990, 10:4456-4465.
[17] Jia G, Fu Y, Zhao X, et al.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J]. Nat Chem Biol, 2011, 7:885-887.
[18] Bokar JA, Shambaugh ME, Polayes D, et al.Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA(N6-adenosine)-methyltransferase[J]. RNA, 1997, 3:1233-1247.
[19] Liu J, Yue Y, Han D, et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J]. Nat Chem Biol, 2014, 10:93-95.
[20] Ping XL, Sun BF, Wang L, et al.Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J]. Cell Res, 2014, 24:177-189.
[21] Liu ZX, Li LM, Sun HL, et al.Link Between m6A Modification and Cancers[J]. Front Bioeng Biotechnol, 2018, 6:89.
[22] Yue Y, Liu J, Cui X, et al.VIRMA mediates preferential m(6)A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation[J]. Cell Discov, 2018, 4:10.
[23] Wen J, Lv R, Ma H, et al.Zc3h13 regulates nuclear RNA m⁶ a methylation and mouse embryonic stem cell self-renewal[J]. Mol Cell, 2018, 69:1028-1038.
[24] Warda AS, Kretschmer J, Hackert P, et al.Human METTL16 is a N⁶-methyladenosine(m⁶A)methyltransferase that targets pre-mRNAs and various non-coding RNAs[J]. EMBO Rep, 2017, 18:2004-2014.
[25] Pendleton KE, Chen B, Liu K, et al. The U6 snRNA m⁶A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention[J]. Cell, 2017, 169:824-835. e814.
[26] Fedeles BI, Singh V, Delaney JC, et al.The AlkB Family of Fe(II)/alpha-Ketoglutarate-dependent Dioxygenases:Repairing Nucleic Acid Alkylation Damage and Beyond[J]. J Biol Chem, 2015, 290:20734-20742.
[27] Zheng G, Dahl JA, Niu Y, et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Mol Cell, 2013, 49:18-29.
[28] Wang X, Lu Z, Gomez A, et al.N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505:117-120.
[29] Hsu PJ, Zhu Y, Ma H, et al.Ythdc2 is an N⁶-methyladenosine binding protein that regulates mammalian spermatogenesis[J]. Cell Res, 2017, 27:1115-1127.
[30] Alarcon CR, Goodarzi H, Lee H, et al.HNRNPA2B1 is a mediator of m⁶ a-dependent nuclear RNA processing events[J]. Cell, 2015, 162:1299-1308.
[31] Liu N, Dai Q, Zheng G, et al.N⁶ -methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature, 2015, 518:560-564.
[32] Huang H, Weng H, Sun W, et al.Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation[J]. Nat Cell Biol, 2018, 20:285-295.
[33] Fustin JM, Doi M, Yamaguchi Y, et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock[J]. Cell, 2013, 155:793-806.
[34] Lin Z, Hsu PJ, Xing X, et al.Mettl3-/Mettl14-mediated mRNA N(6)-methyladenosine modulates murine spermatogenesis[J]. Cell Res, 2017, 27:1216-1230.
[35] Mendel M, Chen KM, Homolka D, et al.Methylation of structured RNA by the m⁶ a writer METTL16 is essential for mouse embryonic development[J]. Mol Cell, 2018, 71:986-1000.
[36] Aguilo F, Zhang F, Sancho A, et al.Coordination of m⁶ a mRNA methylation and gene transcription by ZFP217 regulates pluripotency and reprogramming[J]. Cell Stem Cell, 2015, 17:689-704.
[37] Haussmann IU, Bodi Z, Sanchez-Moran E, et al.m⁶ a potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination[J]. Nature, 2016, 540:301-304.
[38] Li HB, Tong J, Zhu S, et al.m⁶ A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways[J]. Nature, 2017, 548:338-342.
[39] Zhou J, Wan J, Gao X, et al.Dynamic m⁶ A mRNA methylation directs translational control of heat shock response[J]. Nature, 2015, 526:591-594.
[40] Mathiyalagan P, Adamiak M, Mayourian J, et al.FTO-dependent m⁶ a regulates cardiac function during remodeling and repair[J]. Circulation, 2019, 139(4):518-532.
[41] Ben-Haim MS, Moshitch-Moshkovitz S, Rechavi G.FTO:linking m6A demethylation to adipogenesis[J]. Cell Res, 2015, 25:3-4.
[42] Shen F, Huang W, Huang JT, et al.Decreased N⁶ -methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5[J]. J Clin Endocrinol Metab, 2015, 100:E148-154.
[43] Angelova MT, Dimitrova DG, Dinges N, et al.The emerging field of epitranscriptomics in neurodevelopmental and neuronal disorders[J]. Front Bioeng Biotechnol, 2018, 6:46.
[44] Ghosh D, Nandi S, Bhattacharjee S.Combination therapy to checkmate Glioblastoma:clinical challenges and advances[J]. Clin Transl Med, 2018, 7:33.
[45] Cui Q, Shi H, Ye P, et al.m⁶ A RNA Methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells[J]. Cell Rep, 2017, 18:2622-2634.
[46] Zhang S, Zhao BS, Zhou A, et al. m⁶ a demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation Program[J]. Cancer Cell, 2017, 31:591-606. e596.
[47] Frohling S, Scholl C, Gilliland DG, et al.Genetics of myeloid malignancies:pathogenetic and clinical implications[J]. J Clin Oncol, 2005, 23:6285-6295.
[48] Vu LP, Pickering BF, Cheng Y, et al.The N⁶-methyladenosine m⁶ A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells[J]. Nat Med, 2017, 23:1369-1376.
[49] Weng H, Huang H, Wu H, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m⁶ a modification[J]. Cell Stem Cell, 2018, 22:191-205. e9.
[50] Barbieri I, Tzelepis K, Pandolfini L, et al.Promoter-bound METTL3 maintains myeloid leukaemia by m⁶ A-dependent translation control[J]. Nature, 2017, 552:126-131.
[51] Bansal H, Yihua Q, Iyer SP, et al.WTAP is a novel oncogenic protein in acute myeloid leukemia[J]. Leukemia, 2014, 28:1171-1174.
[52] Li Z, Weng H, Su R, et al.FTO plays an oncogenic role in acute myeloid leukemia as a N⁶-methyladenosine RNA demethylase[J]. Cancer Cell, 2017, 31:127-141.
[53] Su R, Dong L, Li C, et al.R-2HG exhibits anti-tumor activity by targeting FTO/m⁶ A/MYC/CEBPA signaling[J]. Cell, 2018, 172:90-105.
[54] Bosch FX, Ribes J, Borras J.Epidemiology of primary liver cancer[J]. Semin Liver Dis, 1999, 19:271-285.
[55] Schulze K, Imbeaud S, Letouze E, et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets[J]. Nat Genet, 2015, 47:505-511.
[56] Chen M, Wei L, Law CT, et al.RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2[J]. Hepatology, 2018, 67:2254-2270.
[57] Zhao X, Chen Y, Mao Q, et al.Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma[J]. Cancer Biomark, 2018, 21:859-868.
[58] Yang Z, Li J, Feng G, et al.MicroRNA-145 modulates N⁶-methyladenosine levels by targeting the 3’-untranslated mRNA region of the N⁶-methyladenosine binding YTH domain family 2 protein[J]. J Biol Chem, 2017, 292:3614-3623.
[59] Ma JZ, Yang F, Zhou CC, et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N⁶-methyladenosine-dependent primary MicroRNA processing[J]. Hepatology, 2017, 65:529-543.
[60] Charafe-Jauffret E, Ginestier C, Iovino F, et al.Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature[J]. Cancer Res, 2009, 69:1302-1313.
[61] Creighton CJ, Li X, Landis M, et al.Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features[J]. Proc Natl Acad USA, 2009, 106:13820-13825.
[62] Zhang C, Samanta D, Lu H, et al.Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶ A-demethylation of NANOG mRNA[J]. Proc Natl Acad USA, 2016, 113:E2047-2056.
[63] Zhang C, Zhi WI, Lu H, et al.Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells[J]. Oncotarget, 2016, 7:64527-64542.
[64] Cai X, Wang X, Cao C, et al.HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g[J]. Cancer Lett, 2018, 415:11-19.
[65] Araz O, Ucar EY, Meral M, et al.Frequency of Class I and II HLA alleles in patients with lung cancer according to chemotherapy response and 5-year survival[J]. Clin Respir J, 2015, 9:297-304.
[66] Latimer KM, Mott TF.Lung cancer:diagnosis, treatment principles, and screening[J]. Am Fam Physician, 2015, 91:250-256.
[67] Lin S, Choe J, Du P, et al.The m⁶ a methyltransferase METTL3 promotes translation in human cancer cells[J]. Mol Cell, 2016, 62:335-345.
[68] Du M, Zhang Y, Mao Y, et al.MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA[J]. Biochem Biophys Res Commun, 2017, 482:582-589.
[69] Liu J, Ren D, Du Z, et al.m⁶ a demethylase FTO facilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression[J]. Biochem Biophys Res Commun, 2018, 502:456-464.