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Review
. 2020 Mar 16;37(3):270-288.
doi: 10.1016/j.ccell.2020.02.004.

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

Huilin Huang  1 , Hengyou Weng  2 , Jianjun Chen  3
Affiliations
Review

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

Huilin Huang et al. Cancer Cell. .

Abstract

N6-Methyladenosine (m6A) RNA modification has emerged in recent years as a new layer of regulatory mechanism controlling gene expression in eukaryotes. As a reversible epigenetic modification found not only in messenger RNAs but also in non-coding RNAs, m6A affects the fate of the modified RNA molecules and plays important roles in almost all vital bioprocesses, including cancer development. Here we review the up-to-date knowledge of the pathological roles and underlying molecular mechanism of m6A modifications (in both coding and non-coding RNAs) in cancer pathogenesis and drug response/resistance, and discuss the therapeutic potential of targeting m6A regulators for cancer therapy.

Keywords: N(6)-methyladenosine (m(6)A); RNA modification; cancer epigenetics; cancer stem cells; drug resistance; epitranscriptome; immune therapy; non-coding RNA; prognosis; targeted therapeutics.

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Conflict of interest statement

Declaration of Interests J.C. is the scientific founder of Genovel Biotech Corp. and holds equities with the company.

Figures

Figure 1.
Figure 1.
Reversible m6A modification on mRNA. The adenosine (A) bases reside in mRNA could be methylated to form N6-methyladenosine (m6A) by the large MTC writer complex comprised of the METTL3-METTL14-WTAP core component and other regulatory cofactors or by METTL16 alone. This enzymatic reaction uses S-Adenosyl methionine (SAM) as a methyl donor. m6A could be recognized by m6A binding proteins (readers) to affect mRNA fate, or could be reversibly removed by m6A eraser proteins (i.e., FTO and ALKBH5). The demethylatio process requires α-Ketoglutaric acid (α-KG) and molecular oxygen (O2) as co-substrates and ferrous iron (Fe2+) as a cofactor.
Figure 2.
Figure 2.
Functions of m6A modifications on coding and non-coding RNAs. m6A marks are deposited cotranscriptionally into nascent mRNAs, which undergo alternative splicing with the recruitment of splicing factors to m6A sites or flanking sequences. After splicing, m6A-containing mRNAs are recognized by YTHDC1 and exported into cytoplasm. Existence of m6A on mature mRNAs affects mRNA stability (stabilized by IGF2BP1/2/3 proteins and destabilized by YTHDF2/3 proteins), translation initiation, and translation elongation. m6A marks on lncRNAs play roles in RNA-RNA interaction, RNA-protein interaction, and chromatin remodeling. Anti-sense lncRNAs could modulate m6A abundance on the sense mRNA by recruiting m6A eraser (i.e., ALKBH5). Presence of m6A on pri-miRNA facilitates miRNA processing. In circRNAs, m6A could promote protein synthesis or inhibit circRNA immunity.
Figure 3.
Figure 3.
Deregulation of m6A modifiers in human cancers. Modifiers in red indicate an oncogenic role, modifiers in green indicate a tumor suppressive role, while those in yellow have controversial roles reported, in the specific cancer type. AML, acute myeloid leukemia; BRC, breast cancer; NSCLC, non-small cell lung cancer; GC, gastric cancer; BLC, bladder cancer; PRC, prostate cancer; OST, osteosarcoma; GBM, glioblastoma; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; PAC, pancreatic cancer; CRC, colorectal cancer; GNC, gynecological cancer; CVC, cervical cancer; ENC, endometrial cancer; OVC, ovarian cancer; MLM, melanoma.
Figure 4.
Figure 4.
Causes of aberrant m6A regulation in cancer. Deregulation of the m6A machinery could result in upregulation of oncogenes or downregulation of tumor suppressive genes, leading to cancer development. On the other hand, mutations from other nucleosides to A on mRNA render mRNA to m6A-mediated regulation and can also contribute to cancer. Environmental factors could reprogram the epitranscriptome and lead to cell immortalization.
Figure 5.
Figure 5.
Therapeutic implications of m6A modification. Considering the roles of FTO, ALKBH5, and METTL3 in glioblastoma stem cells (GSCs) and of METTL14 and FTO in leukemia stem cells (LSCs), inhibitors of m6A modifiers holds the potential to be combined with chemotherapy or radiotherapy to erase cancer stem cells (CSCs) and achieve complete remission. In addition, m6A regulators play a role in the immune system, and thus are promising targets for enhancing anti-tumor immunity when combined with immune therapies.
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