N~6-甲基腺嘌呤修饰在临床恶性肿瘤中的研究进展
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摘要
N~6-甲基腺嘌呤(m~6A)是发生于哺乳动物mRNA中最为常见的修饰方式,参与mRNA的剪切、翻译和降解,影响基因的表达。近年来,m~6A修饰及其调控蛋白在肿瘤发生发展中的作用已成为生物医学研究的热点领域之一。现从人体器官系统角度,对m~6A修饰及其调控蛋白在多种肿瘤进程中的作用以及分子机制进行综述。
N~6-methyladenosine(m~6A) is the most common modification in mRNA, which mainly occurs in 3'-UTR region or near stop codon. As an important epigenetic modification, m~6A regulates mRNA stability, splicing and translation to control gene functions. Recently, the regulatory functions of m~6A and its machinery proteins in tumorigenesis have become the hot research area. This review summarized the roles of m~6A in different clinical cancers according to human system organs.
N~6-methyladenosine(m~6A) is the most common modification in mRNA, which mainly occurs in 3'-UTR region or near stop codon. As an important epigenetic modification, m~6A regulates mRNA stability, splicing and translation to control gene functions. Recently, the regulatory functions of m~6A and its machinery proteins in tumorigenesis have become the hot research area. This review summarized the roles of m~6A in different clinical cancers according to human system organs.
引文
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[28]Huang H,Weng H,Sun W,et al.Recognition of RNAN(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.Nat Cell Biol,2018,20:285-95
[29]Liu ZX,Li LM,Sun HL,et al.Link between m6Amodification and cancers.Front Bioeng Biotechnol,2018,6:89
[30]Deng X,Su R,Weng H,et al.RNA N(6)-methyladenosine modification in cancers:current status and perspectives.Cell Res,2018,28:507-17
[31]Zhang S,Zhao BS,Zhou A,et al.m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stemlike cells by sustaining FOXM1 expression and cell proliferation program.Cancer Cell,2017,31:591-606 e6
[32]Cui Q,Shi H,Ye P,et al.m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells.Cell Rep,2017,18:2622-34
[33]Visvanathan A,Patil V,Arora A,et al.Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance.Oncogene,2018,37:522-33
[34]Yang J,Loos RJ,Powell JE,et al.FTO genotype is associated with phenotypic variability of body mass index.Nature,2012,490:267-72
[35]Li Z,Weng H,Su R,et al.FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNAdemethylase.Cancer Cell,2017,31:127-41
[36]Losman JA,Looper RE,Koivunen P,et al.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.Science,2013,339:1621-5
[37]Rohle D,Popovici-Muller J,Palaskas N,et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.Science,2013,340:626-30
[38]Wang F,Travins J,DeLaBarre B,et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.Science,2013,340:622-6
[39]Su R,Dong L,Li C,et al.R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling.Cell,2018,172:90-105
[40]Vu LP,Pickering BF,Cheng Y,et al.The N(6)-methyladenosine(m(6)A)-forming enzyme METTL3controls myeloid differentiation of normal hematopoietic and leukemia cells.Nat Med,2017,23:1369-76
[41]Weng H,Huang H,Wu H,et al.METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification.Cell Stem Cell,2018,22:191-205 e9
[42]Kwok CT,Marshall AD,Rasko JE,et al.Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia.J Hematol Oncol,2017,10:39
[43]Li Z,Qian P,Shao W,et al.Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion.Cell Res,2018,28:904-17
[44]Chen M,Wei L,Law CT,et al.RNA N6-methyladenosine methyltransferase METTL3 promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2.Hepatology,2017,67:2254-70
[45]Zhao X,Chen Y,Mao Q,et al.Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma.Cancer Biomark,2018,21:859-68
[46]He Y,Hu H,Wang Y,et al.ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNAKCNK15-AS1 methylation.Cell Physiol Biochem,2018,48:838-46
[47]Chen J,Sun Y,Xu X,et al.YTH domain family 2orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells.Cell Cycle,2017,16:2259-71
[48]Nishizawa Y,Konno M,Asai A,et al.Oncogene c-Myc promotes epitranscriptome m(6)A reader YTHDF1expression in colorectal cancer.Oncotarget,2018,9:7476-86
[49]Lin S,Choe J,Du P,et al.The m(6)A methyltransferase METTL3 promotes translation in human cancer cells.Mol Cell,2016,62:335-45
[50]Du M,Zhang Y,Mao Y,et al.MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3m RNA.Biochem Biophys Res Commun,2017,482:582-9
[51]Liu J,Ren D,Du Z,et al.m(6)A demethylase FTOfacilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression.Biochem Biophys Res Commun,2018,502:456-64
[52]Zhang C,Samanta D,Lu H,et al.Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOGmRNA.Proc Natl Acad Sci USA,2016,113:E2047-56
[53]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.Oncotarget,2016,7:64527-42
[54]Cai X,Wang X,Cao C,et al.HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g.Cancer Lett,2018,415:11-9
[55]Zhou S,Bai ZL,Xia D,et al.FTO regulates the chemoradiotherapy resistance of cervical squamous cell carcinoma(CSCC)by targetingβ-catenin through mRNA demethylation.Mol Carcinog,2018,57:590-7
[56]Liu J,Eckert MA,Harada BT,et al.m(6)A mRNAmethylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.Nat Cell Biol,2018,20:1074-83
[57]Li J,Meng S,Xu M,et al.Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels.Oncotarget,2018,9:3752-64
[58]Li X,Tang J,Huang W,et al.The m6A methyltransferase METTL3:acting as a tumor suppressor in renal cell carcinoma.Oncotarget,2017,8:96103-16
[2]Yue Y,Liu J,He C.RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation.Genes Dev,2015,29:1343-55
[3]Dominissini D,Moshitch-Moshkovitz S,Schwartz S,et al.Topology of the human and mouse m6A RNAmethylomes revealed by m6A-seq.Nature,2012,485:201-6
[4]Meyer KD,Saletore Y,Zumbo P,et al.Comprehensive analysis of mRNA methylation reveals enrichment in 3UTRs and near stop codons.Cell,2012,149:1635-46
[5]Luo GZ,MacQueen A,Zheng G,et al.Unique features of the m6A methylome in Arabidopsis thaliana.Nat Commun,2014,5:5630
[6]Wei LH,Song P,Wang Y,et al.The m(6)A reader ECT2controls trichome morphology by affecting mRNAstability in Arabidopsis.Plant Cell,2018,30:968-85
[7]Jia G,Fu Y,Zhao X,et al.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.Nat Chem Biol,2011,7:885-7
[8]Zheng G,Dahl JA,Niu Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.Mol Cell,2013,49:18-29
[9]Fu Y,Jia G,Pang X,et al.FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA.Nat Commun,2013,4:1798
[10]Zhu T,Roundtree IA,Wang P,et al.Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine.Cell Res,2014,24:1493-6
[11]张笑,贾桂芳.RNA表观遗传修饰:N~6-甲基腺嘌呤.遗传,2016,38:275-88
[12]Bokar JA,Shambaugh ME,Polayes D,et al.Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA(N6-adenosine)-methyltransferase.RNA,1997,3:1233-47
[13]Liu J,Yue Y,Han D,et al.A METTL3-METTL14complex mediates mammalian nuclear RNA N6-adenosine methylation.Nat Chem Biol,2014,10:93-5
[14]Ping XL,Sun BF,Wang L,et al.Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.Cell Res,2014,24:177-89
[15]Schwartz S,Mumbach MR,Jovanovic M,et al.Perturbation of m6A writers reveals two distinct classes of m RNA methylation at internal and 5'sites.Cell Rep,2014,8:284-96
[16]Aguilo F,Zhang F,Sancho A,et al.Coordination of m(6)A mRNA methylation and gene transcription by ZFP217regulates pluripotency and reprogramming.Cell Stem Cell,2015,17:689-704
[17]Patil DP,Chen CK,Pickering BF,et al.m(6)A RNAmethylation promotes XIST-mediated transcriptional repression.Nature,2016,537:369-73
[18]Alarcon CR,Lee H,Goodarzi H,et al.N6-methyladenosine marks primary microRNAs for processing.Nature,2015,519:482-5
[19]Alarcon CR,Goodarzi H,Lee H,et al.HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events.Cell,2015,162:1299-308
[20]Ma JZ,Yang F,Zhou CC,et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary microRNA processing.Hepatology,2017,65:529-43
[21]Loos RJ,Yeo GS.The bigger picture of FTO:the first GWAS-identified obesity gene.Nat Rev Endocrinol,2014,10:51-61
[22]Church C,Moir L,McMurray F,et al.Overexpression of Fto leads to increased food intake and results in obesity.Nat Genet,2010,42:1086-92
[23]Thalhammer A,Bencokova Z,Poole R,et al.Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor1α(HIF-1α).PLoS One,2011,6:e16210
[24]Wang X,Lu Z,Gomez A,et al.N6-methyladenosinedependent regulation of messenger RNA stability.Nature,2014,505:117-20
[25]Xu C,Wang X,Liu K,et al.Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain.Nat Chem Biol,2014,10:927-9
[26]Xiao W,Adhikari S,Dahal U,et al.Nuclear m(6)A reader YTHDC1 regulates mRNA splicing.Mol Cell,2016,61:507-19
[27]Meyer KD,Patil DP,Zhou J,et al.5'UTR m(6)Apromotes cap-independent translation.Cell,2015,163:999-1010
[28]Huang H,Weng H,Sun W,et al.Recognition of RNAN(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.Nat Cell Biol,2018,20:285-95
[29]Liu ZX,Li LM,Sun HL,et al.Link between m6Amodification and cancers.Front Bioeng Biotechnol,2018,6:89
[30]Deng X,Su R,Weng H,et al.RNA N(6)-methyladenosine modification in cancers:current status and perspectives.Cell Res,2018,28:507-17
[31]Zhang S,Zhao BS,Zhou A,et al.m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stemlike cells by sustaining FOXM1 expression and cell proliferation program.Cancer Cell,2017,31:591-606 e6
[32]Cui Q,Shi H,Ye P,et al.m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells.Cell Rep,2017,18:2622-34
[33]Visvanathan A,Patil V,Arora A,et al.Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance.Oncogene,2018,37:522-33
[34]Yang J,Loos RJ,Powell JE,et al.FTO genotype is associated with phenotypic variability of body mass index.Nature,2012,490:267-72
[35]Li Z,Weng H,Su R,et al.FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNAdemethylase.Cancer Cell,2017,31:127-41
[36]Losman JA,Looper RE,Koivunen P,et al.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible.Science,2013,339:1621-5
[37]Rohle D,Popovici-Muller J,Palaskas N,et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.Science,2013,340:626-30
[38]Wang F,Travins J,DeLaBarre B,et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.Science,2013,340:622-6
[39]Su R,Dong L,Li C,et al.R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling.Cell,2018,172:90-105
[40]Vu LP,Pickering BF,Cheng Y,et al.The N(6)-methyladenosine(m(6)A)-forming enzyme METTL3controls myeloid differentiation of normal hematopoietic and leukemia cells.Nat Med,2017,23:1369-76
[41]Weng H,Huang H,Wu H,et al.METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification.Cell Stem Cell,2018,22:191-205 e9
[42]Kwok CT,Marshall AD,Rasko JE,et al.Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia.J Hematol Oncol,2017,10:39
[43]Li Z,Qian P,Shao W,et al.Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion.Cell Res,2018,28:904-17
[44]Chen M,Wei L,Law CT,et al.RNA N6-methyladenosine methyltransferase METTL3 promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2.Hepatology,2017,67:2254-70
[45]Zhao X,Chen Y,Mao Q,et al.Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma.Cancer Biomark,2018,21:859-68
[46]He Y,Hu H,Wang Y,et al.ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNAKCNK15-AS1 methylation.Cell Physiol Biochem,2018,48:838-46
[47]Chen J,Sun Y,Xu X,et al.YTH domain family 2orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells.Cell Cycle,2017,16:2259-71
[48]Nishizawa Y,Konno M,Asai A,et al.Oncogene c-Myc promotes epitranscriptome m(6)A reader YTHDF1expression in colorectal cancer.Oncotarget,2018,9:7476-86
[49]Lin S,Choe J,Du P,et al.The m(6)A methyltransferase METTL3 promotes translation in human cancer cells.Mol Cell,2016,62:335-45
[50]Du M,Zhang Y,Mao Y,et al.MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3m RNA.Biochem Biophys Res Commun,2017,482:582-9
[51]Liu J,Ren D,Du Z,et al.m(6)A demethylase FTOfacilitates tumor progression in lung squamous cell carcinoma by regulating MZF1 expression.Biochem Biophys Res Commun,2018,502:456-64
[52]Zhang C,Samanta D,Lu H,et al.Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOGmRNA.Proc Natl Acad Sci USA,2016,113:E2047-56
[53]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.Oncotarget,2016,7:64527-42
[54]Cai X,Wang X,Cao C,et al.HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g.Cancer Lett,2018,415:11-9
[55]Zhou S,Bai ZL,Xia D,et al.FTO regulates the chemoradiotherapy resistance of cervical squamous cell carcinoma(CSCC)by targetingβ-catenin through mRNA demethylation.Mol Carcinog,2018,57:590-7
[56]Liu J,Eckert MA,Harada BT,et al.m(6)A mRNAmethylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.Nat Cell Biol,2018,20:1074-83
[57]Li J,Meng S,Xu M,et al.Downregulation of N(6)-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N(6)-methyladenosine levels.Oncotarget,2018,9:3752-64
[58]Li X,Tang J,Huang W,et al.The m6A methyltransferase METTL3:acting as a tumor suppressor in renal cell carcinoma.Oncotarget,2017,8:96103-16