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Importance of m N6-methyladenosine (m6A) RNA modification in cancer

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Abstract

RNA methylation, which was identified back in 1970s, has gained remarkable interest in recent years as it was shown to be a reversible modification involved in many cellular processes like mRNA and miRNA processing, mRNA localisation, translation suppression, or activation. These, in turn, affect important bioprocesses such as tissue development, sex determination, and DNA damage response. Important group of proteins are responsible for adding, recognizing, and removing the methyl group to and from the RNA molecules, which are referred as writers, readers, and erasers, respectively. If any of the processes is not strictly controlled, this can cause abnormalities in gene expression, which result in diseases including cancers such as lung, pancreas, glioblastoma, and breast cancer. Mechanisms of RNA methylation and its role in various cancer types and diagnostic methods for RNA methylation are discussed in this article.

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References

  1. Moore LD, Le T, Fan G. DNA methylation its basic function. Neuropsychopharmacology 2013;38(1):23–38.

    Article  CAS  Google Scholar 

  2. Torres IO, Fujimori DG. Functional coupling between writers, erasers and readers of histone and DNA methylation. Curr Opin Struct Biol. 2015;35:68–75.

    Article  CAS  Google Scholar 

  3. Curradi M, et al. Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol. 2002;22(9):3157–73.

    Article  CAS  Google Scholar 

  4. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012;13(5):343–57.

    Article  CAS  Google Scholar 

  5. EPIGENTEK. RNA methylation analysis made easy. 2010 http://dx.doi.org/10.1093/nar/gkp1117.

  6. Liu J, Jia G. Methylation modifications in eukaryotic messenger RNA. J Genet Genomics. 2014;41(1):21–33.

    Article  CAS  Google Scholar 

  7. Roignant JY, Soller M. m(6)A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet. 2017;33(6):380–90.

    Article  CAS  Google Scholar 

  8. Deng X, et al. Role of N(6)-methyladenosine modification in cancer. Curr Opin Genet Dev. 2018;48:1–7.

    Article  CAS  Google Scholar 

  9. Boccaletto P, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 2018;46(D1):D303-d307.

    Article  Google Scholar 

  10. Squires JE, et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 2012;40(11):5023–33.

    Article  CAS  Google Scholar 

  11. Motorin Y, Lyko F, Helm M. 5-Methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res. 2010;38(5):1415–30.

    Article  CAS  Google Scholar 

  12. Amort T, et al. Distinct 5-methylcytosine profiles in poly(A) RNA from mouse embryonic stem cells and brain. Genome Biol. 2017. 18(1).

  13. Helm M. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34(2):721–33.

    Article  CAS  Google Scholar 

  14. Pan Y, et al. Multiple functions of m6A RNA methylation in cancer. J Hematol Oncol 2018;11(1):48.

  15. Zhou KI, Pan T. Structures of the m6A methyltransferase complex: two subunits with distinct but coordinated roles. Mol Cell. 2016;63(2):183–5.

    Article  CAS  Google Scholar 

  16. Ping XL, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24(2):177–89.

    Article  CAS  Google Scholar 

  17. Zheng G, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29.

    Article  CAS  Google Scholar 

  18. Jia G, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885–7.

    Article  CAS  Google Scholar 

  19. Jia G, Fu Y, He C. Reversible RNA adenosine methylation in biological regulation. Trends Genet. 2013;29(2):108–15.

    Article  CAS  Google Scholar 

  20. Wang X, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117–20.

    Article  Google Scholar 

  21. Wang X, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–99.

    Article  CAS  Google Scholar 

  22. Shi H, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017;27(3):315–28.

    Article  CAS  Google Scholar 

  23. Meyer KD, et al. 5′ UTR m(6)A promotes cap-independent translation. Cell. 2015;163(4):999–1010.

    Article  CAS  Google Scholar 

  24. Alarcon CR, et al. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162(6):1299–308.

    Article  CAS  Google Scholar 

  25. Liu N, et al. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518(7540):560–4.

    Article  CAS  Google Scholar 

  26. Jaffrey SR, Kharas MG. Emerging links between m6A and misregulated mRNA methylation in cancer. Genome Med. 2017. 9.

  27. Vu LP, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23(11):1369–76.

    Article  CAS  Google Scholar 

  28. Weng H, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell. 2018;22(2):191–205.e9.

    Article  CAS  Google Scholar 

  29. Li Z, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–41.

    Article  Google Scholar 

  30. Mochizuki S, Okada Y. ADAMs in cancer cell proliferation progression. Cancer Sci. 2007;98(5):621–8.

    Article  CAS  Google Scholar 

  31. Cui Q, et al. m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18(11):2622–34.

    Article  CAS  Google Scholar 

  32. Zhang S, et al. m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606.e6.

    Article  CAS  Google Scholar 

  33. Li Y, Zhang S, Huang S. FoxM1: a potential drug target for glioma. Future Oncol. 2012;8(3):223–6.

    Article  CAS  Google Scholar 

  34. Zhang C, et al., 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 2016. 113(14):E2047-56

    Article  Google Scholar 

  35. Cai X, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7 g. Cancer Lett. 2018;415:11–9.

    Article  CAS  Google Scholar 

  36. Chen M, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology. 2018;67(6):2254–70.

    Article  CAS  Google Scholar 

  37. Chen J, et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle. 2017;16(23):2259–71.

    Article  CAS  Google Scholar 

  38. Yuan S, et al. Methylation by NSun2 represses the levels and function of microRNA 125b. Mol Cell Biol. 2014;34(19):3630–41.

    Article  Google Scholar 

  39. Pollex T, Hanna K, Schaefer M. Detection of cytosine methylation in RNA using bisulfite sequencing. Cold Spring Harb Protoc 2010. 2010(10): p. pdb.prot5505.

  40. Peer E, Rechavi G, Dominissini D. Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr Opin Chem Biol. 2017;41:93–8.

    Article  CAS  Google Scholar 

  41. Dominissini D, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-sEq. Nature. 2012;485(7397):201–6.

    Article  CAS  Google Scholar 

  42. Linder B, et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat Methods. 2015;12(8):767–72.

    Article  CAS  Google Scholar 

  43. Schwartz S, Motorin Y. Next-generation sequencing technologies for detection of modified nucleotides in RNAs. RNA Biol. 2017;14(9):1124–37.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Medicine, Faculty of Medicine, Near East University, 99138, Nicosia, Cyprus

    Gulten Tuncel

  2. Department of Medical Genetics, Faculty of Medicine, Near East University, 99138, Nicosia, Cyprus

    Rasime Kalkan

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  1. Gulten Tuncel
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  2. Rasime Kalkan
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Correspondence to Rasime Kalkan.

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Tuncel, G., Kalkan, R. Importance of m N6-methyladenosine (m6A) RNA modification in cancer. Med Oncol 36, 36 (2019). https://doi.org/10.1007/s12032-019-1260-6

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  • DOI: https://doi.org/10.1007/s12032-019-1260-6

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