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PMID: 29374143 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Review

N6-methyladenosine links RNA metabolism to cancer progression.

Cell death & disease ·Vol. 9 ·No. 2 ·2018-00-26 ·Pages 124

Dai D, Wang H, Zhu L, Jin H, Wang X

Abstract

N6-methyladenosine (m6A) is the most abundant mRNA modification. With the development of antibody-based sequencing technologies and the findings of m6A-related "writers", "erasers", and "readers", the relationships between m6A and mRNA metabolism are emerging. The m6A modification influences almost every step of RNA metabolism that comprises mRNA processing, mRNA exporting from nucleus to cytoplasm, mRNA translation, mRNA decay, and the biogenesis of long-non-coding RNA (lncRNA) and microRNA (miRNA). Recently, more and more studies have found m6A is associated with cancer, contributing to the self-renewal of cancer stem cell, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy. Inhibitors of m6A-related factors have been explored, and some of them were identified to inhibit cancer progression, indicating that m6A could be a target for cancer therapy. In this review, we are trying to summarize the regulation and function of m6A in human carcinogenesis.

MeSH Terms
Adenosine/analogs & derivatives,metabolism Animals DNA Damage Disease Progression Humans Neoplasms/genetics,metabolism,pathology RNA, Long Noncoding/genetics,metabolism RNA, Neoplasm/metabolism
Chemicals
RNA, Long Noncoding RNA, Neoplasm N-methyladenosine Adenosine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Dai Dongjun
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Wang Hanying
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Zhu Liyuan
Laboratory of Cancer Biology, Key Lab of Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Jin Hongchuan
Laboratory of Cancer Biology, Key Lab of Biotherapy, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China. jinhc@zju.edu.cn.
Wang Xian
Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China. wangx118@zju.edu.cn.
References (105)
105 references, click to expand
  1. L-methionine availability regulates expression of the methionine adenosyltransferase 2A gene in human hepatocarcinoma cells: role of S-adenosylmethionine.
    J Biol Chem. 2003 May 30;278(22):19885-90 PMID: 12660248
  2. Sequences containing methylated nucleotides at the 5' termini of messenger RNAs: possible implications for processing.
    Cell. 1974 Nov;3(3):197-9 PMID: 4373171
  3. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.
    Cell Res. 2014 Dec;24(12 ):1403-19 PMID: 25412662
  4. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.
    Cell. 2015 Jun 4;161(6):1388-99 PMID: 26046440
  5. Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells.
    Mol Cancer. 2012 Mar 21;11:13 PMID: 22436134
  6. Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma.
    J Gastroenterol Hepatol. 2013 Mar;28(3):565-75 PMID: 22989374
  7. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
    Nature. 2012 Aug 16;488(7411):404-8 PMID: 22842901
  8. Emerging role of nanog in tumorigenesis and cancer stem cells.
    Int J Cancer. 2014 Dec 15;135(12 ):2741-8 PMID: 24375318
  9. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome.
    Nat Methods. 2015 Aug;12(8):767-72 PMID: 26121403
  10. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells.
    Cell Stem Cell. 2014 Dec 4;15(6):707-19 PMID: 25456834
  11. miR-29b inhibits the progression of esophageal squamous cell carcinoma by targeting MMP-2.
    Neoplasma. 2015 ;62(3):384-90 PMID: 25866219
  12. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA.
    Cell Res. 2017 Mar;27(3):315-328 PMID: 28106072
  13. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate-dependent nucleic acid demethylase.
    J Med Chem. 2012 Mar 8;55(5):2173-84 PMID: 22263962
  14. Spliceosome structure and function.
    Cold Spring Harb Perspect Biol. 2011 Jul 01;3(7):null PMID: 21441581
  15. Dissecting the expression landscape of RNA-binding proteins in human cancers.
    Genome Biol. 2014 Jan 10;15(1):R14 PMID: 24410894
  16. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.
    RNA. 1997 Nov;3(11):1233-47 PMID: 9409616
  17. Long noncoding RNAs: cellular address codes in development and disease.
    Cell. 2013 Mar 14;152(6):1298-307 PMID: 23498938
  18. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.
    Nucleic Acids Res. 2015 Jan;43(1):373-84 PMID: 25452335
  19. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor.
    J Am Chem Soc. 2012 Oct 31;134(43):17963-71 PMID: 23045983
  20. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
    Mol Cell. 2013 Jan 10;49(1):18-29 PMID: 23177736
  21. 5' UTR m(6)A Promotes Cap-Independent Translation.
    Cell. 2015 Nov 5;163(4):999-1010 PMID: 26593424
  22. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
    Nat Chem Biol. 2011 Oct 16;7(12 ):885-7 PMID: 22002720
  23. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine.
    EMBO J. 2017 May 15;36(10 ):1302-1315 PMID: 28420743
  24. Structural basis for inhibition of the fat mass and obesity associated protein (FTO).
    J Med Chem. 2013 May 9;56(9):3680-8 PMID: 23547775
  25. N6-methyladenosine-dependent regulation of messenger RNA stability.
    Nature. 2014 Jan 2;505(7481):117-20 PMID: 24284625
  26. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.
    Hum Mol Genet. 2004 Nov 15;13(22):2803-11 PMID: 15385440
  27. MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3'-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein.
    J Biol Chem. 2017 Mar 3;292(9):3614-3623 PMID: 28104805
  28. A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism.
    Cell Rep. 2016 Aug 16;16(7):1891-902 PMID: 27477275
  29. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond.
    J Biol Chem. 2015 Aug 21;290(34):20734-42 PMID: 26152727
  30. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid.
    Biochemistry. 1977 Apr 19;16(8):1672-6 PMID: 856255
  31. An integrated genomic analysis of human glioblastoma multiforme.
    Science. 2008 Sep 26;321(5897):1807-12 PMID: 18772396
  32. Paroxysmal nocturnal hemoglobinuria: report of one case.
    Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1989 Sep-Oct;30(5):323-5 PMID: 2637613
  33. ASB-2 inhibits growth and promotes commitment in myeloid leukemia cells.
    J Biol Chem. 2002 Jan 4;277(1):218-24 PMID: 11682484
  34. A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases.
    J Am Chem Soc. 2011 Jun 22;133(24):9451-6 PMID: 21585201
  35. ECSASB2 mediates MLL degradation during hematopoietic differentiation.
    Blood. 2012 Feb 2;119(5):1151-61 PMID: 22174154
  36. m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells.
    Cell Rep. 2017 Mar 14;18(11):2622-2634 PMID: 28297667
  37. MicroRNAs in cancer: biomarkers, functions and therapy.
    Trends Mol Med. 2014 Aug;20(8):460-9 PMID: 25027972
  38. Long Noncoding RNAs in Cancer Pathways.
    Cancer Cell. 2016 Apr 11;29(4):452-463 PMID: 27070700
  39. Structure of human RNA N⁶-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.
    Nucleic Acids Res. 2014 Apr;42(7):4741-54 PMID: 24489119
  40. Identification of Wilms' tumor 1-associating protein complex and its role in alternative splicing and the cell cycle.
    J Biol Chem. 2013 Nov 15;288(46):33292-302 PMID: 24100041
  41. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.
    Mol Cell. 2016 Jul 21;63(2):306-317 PMID: 27373337
  42. Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases.
    Angew Chem Int Ed Engl. 2012 Feb 13;51(7):1631-4 PMID: 22241642
  43. Sox2 expression in breast tumours and activation in breast cancer stem cells.
    Oncogene. 2012 Mar 15;31(11):1354-65 PMID: 21822303
  44. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events.
    Cell. 2015 Sep 10;162(6):1299-308 PMID: 26321680
  45. The hnRNP family: insights into their role in health and disease.
    Hum Genet. 2016 Aug;135(8):851-67 PMID: 27215579
  46. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.
    Nat Chem Biol. 2014 Feb;10(2):93-5 PMID: 24316715
  47. Identification of a dehydrogenase acting on D-2-hydroxyglutarate.
    Biochem J. 2004 Jul 1;381(Pt 1):35-42 PMID: 15070399
  48. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.
    Nat Genet. 2008 May;40(5):499-507 PMID: 18443585
  49. Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias.
    J Inherit Metab Dis. 2005;28(6):921-30 PMID: 16435184
  50. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.
    Nature. 2015 Feb 26;518(7540):560-4 PMID: 25719671
  51. MicroRNA: Biogenesis, Function and Role in Cancer.
    Curr Genomics. 2010 Nov;11(7):537-61 PMID: 21532838
  52. Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion.
    Acta Biochim Biophys Sin (Shanghai). 2010 Mar 15;42(3):224-9 PMID: 20213048
  53. Post-transcriptional gene regulation by mRNA modifications.
    Nat Rev Mol Cell Biol. 2017 Jan;18(1):31-42 PMID: 27808276
  54. Crystal structure of the FTO protein reveals basis for its substrate specificity.
    Nature. 2010 Apr 22;464(7292):1205-9 PMID: 20376003
  55. Accumulation of spliced avian retrovirus mRNA is inhibited in S-adenosylmethionine-depleted chicken embryo fibroblasts.
    J Virol. 1982 Jun;42(3):918-31 PMID: 6285005
  56. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6 -methyladenosine-dependent primary MicroRNA processing.
    Hepatology. 2017 Feb;65(2):529-543 PMID: 27774652
  57. Emerging roles of tRNA in adaptive translation, signalling dynamics and disease.
    Nat Rev Genet. 2015 Feb;16(2):98-112 PMID: 25534324
  58. Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.
    Cell Stem Cell. 2015 Dec 3;17 (6):689-704 PMID: 26526723
  59. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing.
    Mol Cell. 2016 Feb 18;61(4):507-519 PMID: 26876937
  60. Glioblastoma Stem Cells as a New Therapeutic Target for Glioblastoma.
    Clin Med Insights Oncol. 2015 Nov 16;9:95-103 PMID: 26617463
  61. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.
    Cell Stem Cell. 2015 Mar 5;16(3):289-301 PMID: 25683224
  62. Overexpression of miR-145-5p inhibits proliferation of prostate cancer cells and reduces SOX2 expression.
    Cancer Invest. 2015 Jul;33(6):251-8 PMID: 25951106
  63. Pharmacological inhibition of FTO.
    PLoS One. 2015 Apr 01;10 (4):e0121829 PMID: 25830347
  64. N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA.
    Mol Cell Biol. 1990 Sep;10(9):4456-65 PMID: 2388614
  65. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.
    Nature. 2012 Apr 29;485(7397):201-6 PMID: 22575960
  66. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex.
    Nat Commun. 2016 Aug 25;7:12626 PMID: 27558897
  67. Current Evidence and Future Perspectives on HuR and Breast Cancer Development, Prognosis, and Treatment.
    Neoplasia. 2016 Nov;18(11):674-688 PMID: 27764700
  68. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶A-demethylation of NANOG mRNA.
    Proc Natl Acad Sci U S A. 2016 Apr 5;113(14 ):E2047-56 PMID: 27001847
  69. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities.
    Cancer Discov. 2013 Jul;3(7):730-41 PMID: 23796461
  70. The emerging role of lncRNAs in cancer.
    Nat Med. 2015 Nov;21(11):1253-61 PMID: 26540387
  71. N6-methyladenosine marks primary microRNAs for processing.
    Nature. 2015 Mar 26;519(7544):482-5 PMID: 25799998
  72. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged.
    Genes Dev. 2010 Nov 1;24(21):2343-64 PMID: 21041405
  73. The molecular hallmarks of epigenetic control.
    Nat Rev Genet. 2016 Aug;17 (8):487-500 PMID: 27346641
  74. miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma.
    J Cancer Res Clin Oncol. 2014 Mar;140(3):387-97 PMID: 24384875
  75. L-2-hydroxyglutaric aciduria, a defect of metabolite repair.
    J Inherit Metab Dis. 2007 Oct;30(5):681-9 PMID: 17603759
  76. Methylated nucleotides block 5' terminus of HeLa cell messenger RNA.
    Cell. 1975 Apr;4(4):379-86 PMID: 164293
  77. m(6)A RNA methylation promotes XIST-mediated transcriptional repression.
    Nature. 2016 Sep 15;537(7620):369-373 PMID: 27602518
  78. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites.
    Cell Rep. 2014 Jul 10;8(1):284-96 PMID: 24981863
  79. Metastatic stem cells: sources, niches, and vital pathways.
    Cell Stem Cell. 2014 Mar 6;14(3):306-21 PMID: 24607405
  80. Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion.
    Oncogene. 2011 May 5;30(18):2161-72 PMID: 21242971
  81. Sequence specificity of mRNA N6-adenosine methyltransferase.
    J Biol Chem. 1990 Nov 25;265(33):20117-22 PMID: 2173695
  82. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells.
    Oncotarget. 2016 Oct 4;7(40):64527-64542 PMID: 27590511
  83. Ribosome heterogeneity in tumorigenesis: the rRNA point of view.
    Mol Cell Oncol. 2015 Mar 24;2(3):e983755 PMID: 27305893
  84. Posttranscriptional regulation of cancer traits by HuR.
    Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29 PMID: 21935886
  85. IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation.
    Cancer Cell. 2017 May 8;31(5):619-620 PMID: 28486104
  86. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation.
    J Biol Chem. 2014 Jun 20;289(25):17299-311 PMID: 24778178
  87. Glioblastoma survival in the United States before and during the temozolomide era.
    J Neurooncol. 2012 Apr;107(2):359-64 PMID: 22045118
  88. Cancer-associated regulation of alternative splicing.
    Nat Struct Mol Biol. 2009 Jun;16(6):670-6 PMID: 19448617
  89. Methyl labeling of HeLa cell hnRNA: a comparison with mRNA.
    Cell. 1976 Feb;7(2):227-37 PMID: 954080
  90. LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress.
    Nat Cell Biol. 2016 Apr;18(4):431-42 PMID: 26999735
  91. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis.
    Cancer Res. 2008 Aug 15;68(16):6533-40 PMID: 18701476
  92. Targeting the DNA Damage Response in Cancer.
    Mol Cell. 2015 Nov 19;60(4):547-60 PMID: 26590714
  93. MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA.
    Biochem Biophys Res Commun. 2017 Jan 22;482(4):582-589 PMID: 27856248
  94. RNA m6A methylation regulates the ultraviolet-induced DNA damage response.
    Nature. 2017 Mar 23;543(7646):573-576 PMID: 28297716
  95. RNA-methylation-dependent RNA processing controls the speed of the circadian clock.
    Cell. 2013 Nov 7;155(4):793-806 PMID: 24209618
  96. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.
    Mol Cell. 2016 May 5;62(3):335-345 PMID: 27117702
  97. Gene expression regulation mediated through reversible m⁶A RNA methylation.
    Nat Rev Genet. 2014 May;15(5):293-306 PMID: 24662220
  98. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
    Cell Res. 2014 Feb;24(2):177-89 PMID: 24407421
  99. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.
    Cancer Cell. 2017 Jan 9;31(1):127-141 PMID: 28017614
  100. Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis.
    Int J Mol Sci. 2013 May 10;14(5):10015-41 PMID: 23665903
  101. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature.
    Cancer Res. 2009 Feb 15;69(4):1302-13 PMID: 19190339
  102. The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention.
    Cell. 2017 May 18;169(5):824-835.e14 PMID: 28525753
  103. Are snoRNAs and snoRNA host genes new players in cancer?
    Nat Rev Cancer. 2012 Jan 19;12 (2):84-8 PMID: 22257949
  104. RNA interference and cancer therapy.
    Pharm Res. 2011 Dec;28(12):2983-95 PMID: 22009588
  105. The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications.
    Amino Acids. 2016 Sep;48(9):2067-80 PMID: 27161106
Article Info
Journal
Cell death & disease
Abbr.
Cell Death Dis
ISSN
2041-4889
DOI
10.1038/s41419-017-0129-x
Email
jinhc@zju.edu.cn
wangx118@zju.edu.cn
Published
2018-00-26
Epub
2018-00-26
Pages
124
Language
English
Region
England
NLM ID
101524092
PMCID
PMC5833385
External Links
PubMed source DOI: 10.1038/s41419-017-0129-x PMC Full Text View journal details
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