Molecular Biology Reports

, Volume 46, Issue 1, pp 1383–1391 | Cite as

Functions of RNA N6-methyladenosine modification in cancer progression

  • Bing Chen
  • Ya Li
  • Ruifeng Song
  • Chen Xue
  • Feng XuEmail author


N6-methyladenosine (m6A) serves as a major RNA methylation modification and impacts the initiation and progression of various human cancers through diverse mechanisms. It has been reported that m6A RNA methylation is involved in different physiological and pathological processes, including stem cell differentiation and motility, immune response, cellular stress, tissue renewal and viral infection. In this review, the m6A modification and its regulatory functions in a few major cancers is introduced. The detection approaches for the m6A sites identification are discussed. Additionally, the potential of the RNA m6A modification in clinical application is discussed.


RNA N6-methyladenosine modification Cancer progression Physiological and pathological processes Detection approaches Clinical application 



We thank the PubMed database and its contributors for this valuable public data set. We also thank Dr Menglong Zhao from Dutch Institute for Fundamental Energy Research for helping to edit this manuscript.

Author contributions

All authors participated in the preparation of the manuscript, read and approved the final manuscript.


This work was supported by the Key Project of Scientific Research Foundation for Colleges and Universities in Henan Province (16A320081) and The National Natural Science Foundation of China (81802325).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Adams J, Cory S (1975) Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA. Nature 255:28–33Google Scholar
  2. 2.
    Adhikari S, Xiao W, Zhao YL, Yang YG (2016) m(6)A: signaling for mRNA splicing. RNA Biol 13:756–759. Google Scholar
  3. 3.
    Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF (2015) HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 162:1299–1308. Google Scholar
  4. 4.
    Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF (2015) N6-methyladenosine marks primary microRNAs for processing. Nature 519:482–485. Google Scholar
  5. 5.
    Aloni Y, Dhar R, Khoury G (1979) Methylation of nuclear simian virus 40 RNAs. J Virol 32:52–60Google Scholar
  6. 6.
    Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, De Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T (2017) Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552:126–131. Google Scholar
  7. 7.
    Beemon K, Keith J (1977) Localization of N6-methyladenosine in the Rous sarcoma virus genome. J Mol Biol 113:165–179Google Scholar
  8. 8.
    Blanco S, Frye M (2014) Role of RNA methyltransferases in tissue renewal and pathology. Current Opin Cell Biol 31:1–7. Google Scholar
  9. 9.
    Blanco S, Dietmann S, Flores JV, Hussain S, Kutter C, Humphreys P, Lukk M, Lombard P, Treps L, Popis M, Kellner S, Holter SM, Garrett L, Wurst W, Becker L, Klopstock T, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Karadottir RT, Helm M, Ule J, Gleeson JG, Odom DT, Frye M (2014) Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J 33:2020–2039. Google Scholar
  10. 10.
    Cao G, Li H, Yin Z, Flavell R (2016) Recent advances in dynamic m6A RNA modification. Open Biol 6:160003Google Scholar
  11. 11.
    Chen J, Odenike O, Rowley JD (2010) Leukaemogenesis: more than mutant genes. Nat Rev Cancer 10:23–36. Google Scholar
  12. 12.
    Chen B, Ye F, Yu L, Jia G, Huang X, Zhang X, Peng S, Chen K, Wang M, Gong S, Zhang R, Yin J, Li H, Yang Y, Liu H, Zhang J, Zhang H, Zhang A, Jiang H, Luo C, Yang C-G (2012) Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J Am Chem Soc 134:17963–17971. Google Scholar
  13. 13.
    Chen M, Wei L, Law C, Tsang F, Shen J, Cheng C, Tsang L, Ho D, Chiu D, Lee J, Wong C, Ng I, Wong C (2017) RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology 67:2254–2270Google Scholar
  14. 14.
    Cui X, Meng J, Zhang S, Chen Y, Huang Y (2016) A novel algorithm for calling mRNA m6A peaks by modeling biological variances in MeRIP-seq data. Bioinformatics 32:i378–i385. Google Scholar
  15. 15.
    Cui X, Meng J, Zhang S, Rao MK, Chen Y, Huang Y (2016) A hierarchical model for clustering m(6)A methylation peaks in MeRIP-seq data. BMC Genom 17(Suppl 7):520. Google Scholar
  16. 16.
    Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z, Huang Y, Yang C-G, Riggs AD, He C, Shi Y (2017) m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep 18:2622–2634. Google Scholar
  17. 17.
    Dai D, Wang H, Zhu L, Jin H, Wang X (2018) N6-methyladenosine links RNA metabolism to cancer progression. Cell Death Dis 9:124. Google Scholar
  18. 18.
    DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A (2017) Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 67:439–448. Google Scholar
  19. 19.
    Desrosiers R, Friderici K, Rottman F (1974) Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci USA 71:3971–3975Google Scholar
  20. 20.
    Dixit D, Xie Q, Rich JN, Zhao JC (2017) Messenger RNA methylation regulates glioblastoma tumorigenesis. Cancer Cell 31:474–475. Google Scholar
  21. 21.
    Dohner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373:1136–1152. Google Scholar
  22. 22.
    Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-sEq. Nature 485:201–206. Google Scholar
  23. 23.
    Dominissini D, Moshitch-Moshkovitz S, Amariglio N, Rechavi G (2015) Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-SEq. Methods Enzymol 560:131–147. Google Scholar
  24. 24.
    Erales J, Marchand V, Panthu B, Gillot S, Belin S, Ghayad SE, Garcia M, Laforets F, Marcel V, Baudin-Baillieu A, Bertin P, Coute Y, Adrait A, Meyer M, Therizols G, Yusupov M, Namy O, Ohlmann T, Motorin Y, Catez F, Diaz JJ (2017) Evidence for rRNA 2′-O-methylation plasticity: control of intrinsic translational capabilities of human ribosomes. Proc Natl Acad Sci USA 114:12934–12939. Google Scholar
  25. 25.
    Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, Tong Y, Cheng C, Chen Z (2014) Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. J Biol Chem 289:11571–11583. Google Scholar
  26. 26.
    Flores JV, Cordero-Espinoza L, Oeztuerk-Winder F, Andersson-Rolf A, Selmi T, Blanco S, Tailor J, Dietmann S, Frye M (2017) Cytosine-5 RNA methylation regulates neural stem cell differentiation and motility. Stem Cell Rep 8:112–124. Google Scholar
  27. 27.
    Fu Y, Dominissini D, Rechavi G, He C (2014) Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet 15:293–306. Google Scholar
  28. 28.
    Gallo R (1971) Transfer RNA and transfer RNA methylation in growing and “resting” adult and embryonic tissues and in various oncogenic systems. Cancer Res 31:621–629Google Scholar
  29. 29.
    Gantt R (1971) In vitro transfer RNA methylation in paired neoplastic and nonneoplastic cell cultures. Cancer Res 31:609–612Google Scholar
  30. 30.
    Genenncher B, Durdevic Z, Hanna K, Zinkl D, Mobin MB, Senturk N, Da Silva B, Legrand C, Carre C, Lyko F, Schaefer M (2018) Mutations in cytosine-5 tRNA methyltransferases impact mobile element expression and genome stability at specific DNA repeats. Cell Rep 22:1861–1874. Google Scholar
  31. 31.
    Genuth NR, Barna M (2018) Heterogeneity and specialized functions of translation machinery: from genes to organisms. Nat Rev Genet. Google Scholar
  32. 32.
    Glasner H, Riml C, Micura R, Breuker K (2017) Label-free, direct localization and relative quantitation of the RNA nucleobase methylations m6A, m5C, m3U, and m5U by top-down mass spectrometry. Nucleic Acids Res 45:8014–8025. Google Scholar
  33. 33.
    Golovina AY, Dzama MM, Petriukov KS, Zatsepin TS, Sergiev PV, Bogdanov AA, Dontsova OA (2014) Method for site-specific detection of m6A nucleoside presence in RNA based on high-resolution melting (HRM) analysis. Nucleic Acids Res 42:e27. Google Scholar
  34. 34.
    He Y, Hu H, Wang Y, Yuan H, Lu Z, Wu P, Liu D, Tian L, Yin J, Jiang K, Miao Y (2018) ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation. Cell Physiol Biochem 48:838–846. Google Scholar
  35. 35.
    Hori H (2017) Transfer RNA methyltransferases with a SpoU-TrmD (SPOUT) fold and their modified nucleosides in tRNA. Biomolecules. Google Scholar
  36. 36.
    Huang Y, Yan J, Li Q, Li J, Gong S, Zhou H, Gan J, Jiang H, Jia G-F, Luo C, Yang C-G (2015) Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res 43:373–384. Google Scholar
  37. 37.
    Huang W, Qi C-B, Lv S-W, Xie M, Feng Y-Q, Huang W-H, Yuan B-F (2016) Determination of DNA and RNA methylation in circulating tumor cells by mass spectrometry. Anal Chem 88:1378–1384. Google Scholar
  38. 38.
    Jaffrey SR, Kharas MG (2017) Emerging links between m(6)A and misregulated mRNA methylation in cancer. Genome Med 9:2. Google Scholar
  39. 39.
    Jain D, Puno M, Meydan C, Lailler N, Mason C, Lima C, Anderson K, Keeney S (2018) Ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2. Elife 7:e30919Google Scholar
  40. 40.
    Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887. Google Scholar
  41. 41.
    Jiang S, Xie Y, He Z, Zhang Y, Zhao Y, Chen L, Zheng Y, Miao Y, Zuo Z, Ren J (2018) m6ASNP: a tool for annotating genetic variants by m6A function. GigaScience. Google Scholar
  42. 42.
    Karijolich J, Yu Y-T (2014) Spliceosomal snRNA modifications and their function. RNA Biol 7:192–204. Google Scholar
  43. 43.
    Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, Vagbo CB, Kussnierczyk A, Klungland A, Darnell JE Jr, Darnell RB (2015) A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev 29:2037–2053. Google Scholar
  44. 44.
    Ke S, Pandya-Jones A, Saito Y, Fak JJ, Vågbø CB, Geula S, Hanna JH, Black DL, Darnell JE, Darnell RB (2017) m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev 31:990–1006. Google Scholar
  45. 45.
    Kwok CT, Marshall AD, Rasko JE, Wong JJ (2017) Genetic alterations of m(6)A regulators predict poorer survival in acute myeloid leukemia. J Hematol Oncol 10:39. Google Scholar
  46. 46.
    Lai W, Jia J, Yan B, Jiang Y, Shi Y, Chen L, Mao C, Liu X, Tang H, Gao M, Cao Y, Liu S, Tao Y (2018) Baicalin hydrate inhibits cancer progression in nasopharyngeal carcinoma by affecting genome instability and splicing. Oncotarget 9:901–914Google Scholar
  47. 47.
    Lathia J, Mack S, Mulkearns-Hubert E, Valentim C, Rich J (2015) Cancer stem cells in glioblastoma. Genes Dev 29:1203–1217Google Scholar
  48. 48.
    Lewinska A, Adamczyk-Grochala J, Deregowska A, Wnuk M (2017) Sulforaphane-induced cell cycle arrest and senescence are accompanied by DNA hypomethylation and changes in microRNA profile in breast cancer cells. Theranostics 7:3461–3477. Google Scholar
  49. 49.
    Li S, Mason CE (2014) The pivotal regulatory landscape of RNA modifications. Annu Rev Genom Hum Genet 15:127–150. Google Scholar
  50. 50.
    Li F, Zhao D, Wu J, Shi Y (2014) Structure of the YTH domain of human YTHDF2 in complex with an m(6)A mononucleotide reveals an aromatic cage for m(6)A recognition. Cell Res 24:1490–1492. Google Scholar
  51. 51.
    Li A, Chen YS, Ping XL, Yang X, Xiao W, Yang Y, Sun HY, Zhu Q, Baidya P, Wang X, Bhattarai DP, Zhao YL, Sun BF, Yang YG (2017) Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res 27:444–447. Google Scholar
  52. 52.
    Li H, Tong J, Zhu S, Batista P, Duffy E, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, Wang G, Broughton J, Chen Y, Kluger Y, Simon M, Chang H, Yin Z, Flavell R (2017) mA mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548:338–342Google Scholar
  53. 53.
    Li X, Tang J, Huang W, Wang F, Li P, Qin C, Qin Z, Zou Q, Wei J, Hua L, Yang H, Wang Z (2017) The M6A methyltransferase METTL3: acting as a tumor suppressor in renal cell carcinoma. Oncotarget 8:96103–96116Google Scholar
  54. 54.
    Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong G-M, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J (2017) FTO Plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell 31:127–141. Google Scholar
  55. 55.
    Li J, Meng S, Xu M, Wang S, He L, Xu X, Wang X, Xie L (2018) Downregulation of N-methyladenosine binding YTHDF2 protein mediated by miR-493-3p suppresses prostate cancer by elevating N-methyladenosine levels. Oncotarget 9:3752–3764Google Scholar
  56. 56.
    Li LJ, Fan YG, Leng RX, Pan HF, Ye DQ (2018) Potential link between m(6)A modification and systemic lupus erythematosus. Mol Immunol 93:55–63. Google Scholar
  57. 57.
    Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE, Jaffrey SR (2015) Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat Methods 12:767–772. Google Scholar
  58. 58.
    Liu N, Parisien M, Dai Q, Zheng G, He C, Pan T (2013) Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19:1848–1856. Google Scholar
  59. 59.
    Long T, Li J, Li H, Zhou M, Zhou XL, Liu RJ, Wang ED (2016) Sequence-specific and shape-selective RNA recognition by the human RNA 5-methylcytosine methyltransferase NSun6. J Biol Chem 291:24293–24303. Google Scholar
  60. 60.
    Loos RJ, Yeo GS (2014) The bigger picture of FTO: the first GWAS-identified obesity gene. Nat Rev Endocrinol 10:51–61. Google Scholar
  61. 61.
    Lu Y, Li S, Zhu S, Gong Y, Shi J, Xu L (2017) Methylated DNA/RNA in body fluids as biomarkers for lung cancer. Biol Proced Online 19:2. Google Scholar
  62. 62.
    Luo S, Tong L (2014) Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. Proc Natl Acad Sci USA 111:13834–13839Google Scholar
  63. 63.
    Maity A, Das B (2016) N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases. FEBS J 283:1607–1630. Google Scholar
  64. 64.
    Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur J-J, Chen Q, Gross SS, Elemento O, Debart F, Kiledjian M, Jaffrey SR (2016) Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541:371–375. Google Scholar
  65. 65.
    Meng J, Lu Z, Liu H, Zhang L, Zhang S, Chen Y, Rao M, Huang Y (2014) A protocol for RNA methylation differential analysis with MeRIP-Seq data and exomePeak R/bioconductor package. Methods 69:274–281Google Scholar
  66. 66.
    Meyer K, Jaffrey S (2017) Rethinking mA readers, writers, and erasers. Annu Rev Cell Dev Biol 33:319–342Google Scholar
  67. 67.
    Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149:1635–1646. Google Scholar
  68. 68.
    Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR (2015) 5′ UTR m(6)A promotes cap-independent translation. Cell 163:999–1010. Google Scholar
  69. 69.
    Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, Kudo T, Hata T, Matsuda C, Mizushima T, Satoh T, Doki Y, Mori M, Ishii H (2018) Oncogene c-Myc promotes epitranscriptome mA reader YTHDF1 expression in colorectal cancer. Oncotarget 9:7476–7486Google Scholar
  70. 70.
    Pan Y, Ma P, Liu Y, Li W, Shu Y (2018) Multiple functions of m(6)A RNA methylation in cancer. J Hematol Oncol 11:48. Google Scholar
  71. 71.
    Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR (2016) m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537:369–373. Google Scholar
  72. 72.
    Patil DP, Pickering BF, Jaffrey SR (2018) Reading m(6)A in the transcriptome: m(6)A-binding proteins. Trends Cell Biol 28:113–127. Google Scholar
  73. 73.
    Peer E, Rechavi G, Dominissini D (2017) Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr Opin Chem Biol 41:93–98. Google Scholar
  74. 74.
    Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, Conrad NK (2017) The U6 snRNA m(6)A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 169:824–835. Google Scholar
  75. 75.
    Perry RP, Kelley DE, Friderici K, Rottman F (1975) The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5′ terminus. Cell 4:387–394Google Scholar
  76. 76.
    Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24:177–189. Google Scholar
  77. 77.
    Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, Sanjana NE, Freinkman E, Pacold ME, Satija R, Mikkelsen TS, Hacohen N, Zhang F, Carr SA, Lander ES, Regev A (2014) Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 8:284–296. Google Scholar
  78. 78.
    Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C (2017) YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res 27:315–328. Google Scholar
  79. 79.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30. Google Scholar
  80. 80.
    Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C, Yu M, Skibbe J, Dai Q, Zou D, Wu T, Yu K, Weng H, Huang H, Ferchen K, Qin X, Zhang B, Qi J, Sasaki AT, Plas DR, Bradner JE, Wei M, Marcucci G, Jiang X, Mulloy JC, Jin J, He C, Chen J (2018) R-2HG exhibits anti-tumor activity by targeting FTO/m 6 A/MYC/CEBPA signaling. Cell 172:90–105. Google Scholar
  81. 81.
    Taketo K, Konno M, Asai A, Koseki J, Toratani M, Satoh T, Doki Y, Mori M, Ishii H, Ogawa K (2018) The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol 52:621–629. Google Scholar
  82. 82.
    Tirumuru N, Zhao BS, Lu W, Lu Z, He C, Wu L (2016) N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 gag protein expression. Elife. Google Scholar
  83. 83.
    Traube FR, Carell T (2017) The chemistries and consequences of DNA and RNA methylation and demethylation. RNA Biol 14:1099–1107. Google Scholar
  84. 84.
    Turkington R (1971) The regulation of transfer RNA methylation in normal and neoplastic mammary cells. Cancer Res 31:644–646Google Scholar
  85. 85.
    Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K (2017) Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37:522–533. Google Scholar
  86. 86.
    Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C (2014) N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505:117–120. Google Scholar
  87. 87.
    Wang P, Doxtader KA, Nam Y (2016) Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 63:306–317. Google Scholar
  88. 88.
    Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P (2016) Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature 534:575–578. Google Scholar
  89. 89.
    Wang S, Sun C, Li J, Zhang E, Ma Z, Xu W, Li H, Qiu M, Xu Y, Xia W, Xu L, Yin R (2017) Roles of RNA methylation by means of N6-methyladenosine (m6A) in human cancers. Cancer Lett 408:112–120. Google Scholar
  90. 90.
    Wang X, Huang J, Zou T, Yin P (2017) Human m(6)A writers: two subunits, 2 roles. RNA Biol 14:300–304. Google Scholar
  91. 91.
    Wang X, Li Z, Kong B, Song C, Cong J, Hou J, Wang S (2017) Reduced mA mRNA methylation is correlated with the progression of human cervical cancer. Oncotarget 8:98918–98930Google Scholar
  92. 92.
    Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C, Sheng Y, Wang Y, Wunderlich M, Zhang B, Dore LC, Su R, Deng X, Ferchen K, Li C, Sun M, Lu Z, Jiang X, Marcucci G, Mulloy JC, Yang J, Qian Z, Wei M, He C, Chen J (2018) METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell 22:191–205. Google Scholar
  93. 93.
    Wojtas MN, Pandey RR, Mendel M, Homolka D, Sachidanandam R, Pillai RS (2017) Regulation of m(6)A transcripts by the 3′→5′ RNA helicase YTHDC2 is essential for a successful meiotic program in the mammalian germline. Mol Cell 68:374–387. Google Scholar
  94. 94.
    Xu C, Liu K, Tempel W, Demetriades M, Aik W, Schofield CJ, Min J (2014) Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. J Biol Chem 289:17299–17311. Google Scholar
  95. 95.
    Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li Y, Lu Z, He C, Min J (2014) Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat Chem Biol 10:927–929. Google Scholar
  96. 96.
    Xu C, Liu K, Ahmed H, Loppnau P, Schapira M, Min J (2015) Structural basis for the discriminative recognition of N6-methyladenosine RNA by the human YT521-B homology domain family of proteins. J Biol Chem 290:24902–24913. Google Scholar
  97. 97.
    You Y, Liu L, Zhang M, Zhu Y, He L, Li D, Zhang J (2014) Genomic characterization of a Helicobacter pylori isolate from a patient with gastric cancer in China. Gut Pathog 6:5. Google Scholar
  98. 98.
    Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, Rafalska I, Heinrich B, Bujnicki JM, Allain FH, Stamm S (2010) The YTH domain is a novel RNA binding domain. J Biol Chem 285:14701–14710. Google Scholar
  99. 99.
    Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA 113:E2047–E2056. Google Scholar
  100. 100.
    Zhang C, Zhi WI, Lu H, Samanta D, Chen I, Gabrielson E, Semenza GL (2016) Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget 7:64527–64542. Google Scholar
  101. 101.
    Zhang S, Zhang S, Liu L, Meng J, Huang Y (2016) m6A-Driver: identifying context-specific mRNA m6A methylation-driven gene interaction networks. PLoS Comput Biol 12:e1005287Google Scholar
  102. 102.
    Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, Majumder S, He C, Huang S (2017) m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31:591–606. Google Scholar
  103. 103.
    Zhao X, Yang Y, Sun BF, Shi Y, Yang X, Xiao W, Hao YJ, Ping XL, Chen YS, Wang WJ, Jin KX, Wang X, Huang CM, Fu Y, Ge XM, Song SH, Jeong HS, Yanagisawa H, Niu Y, Jia GF, Wu W, Tong WM, Okamoto A, He C, Rendtlew Danielsen JM, Wang XJ, Yang YG (2014) FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24:1403–1419. Google Scholar
  104. 104.
    Zhao X, Chen Y, Mao Q, Jiang X, Jiang W, Chen J, Xu W, Zhong L, Sun X (2018) Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Biomark 21:859–868. Google Scholar
  105. 105.
    Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49:18–29. Google Scholar
  106. 106.
    Zheng Y, Nie P, Peng D, He Z, Liu M, Xie Y, Miao Y, Zuo Z, Ren J (2018) m6AVar: a database of functional variants involved in m6A modification. Nucleic Acids Res 46:D139–D145. Google Scholar
  107. 107.
    Zhou KI, Parisien M, Dai Q, Liu N, Diatchenko L, Sachleben JR, Pan T (2016) N(6)-methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding. J Mol Biol 428:822–833. Google Scholar
  108. 108.
    Zhou S, Bai ZL, Xia D, Zhao ZJ, Zhao R, Wang YY, Zhe H (2018) FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting beta-catenin through mRNA demethylation. Mol Carcinog 57:590–597. Google Scholar
  109. 109.
    Zhu T, Roundtree IA, Wang P, Wang X, Wang L, Sun C, Tian Y, Li J, He C, Xu Y (2014) Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res 24:1493–1496. Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Bing Chen
    • 1
  • Ya Li
    • 1
  • Ruifeng Song
    • 1
  • Chen Xue
    • 2
  • Feng Xu
    • 1
    Email author
  1. 1.Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China
  2. 2.Department of Infectious DiseasesThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China

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