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Review
. 2018 May;28(5):507-517.
doi: 10.1038/s41422-018-0034-6. Epub 2018 Apr 23.

RNA N6-methyladenosine modification in cancers: current status and perspectives

Xiaolan Deng  1   2   3 , Rui Su  4   5 , Hengyou Weng  4   5 , Huilin Huang  4   5 , Zejuan Li  6 , Jianjun Chen  7   8
Affiliations
Review

RNA N6-methyladenosine modification in cancers: current status and perspectives

Xiaolan Deng et al. Cell Res. 2018 May.

Abstract

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, and maternal-to-zygotic transition. The m6A modification is deposited by the m6A methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 and WTAP, and probably also VIRMA and RBM15, and can be removed by m6A demethylases (i.e., erasers) such as FTO and ALKBH5. The fates of m6A-modified mRNAs rely on the functions of distinct proteins that recognize them (i.e., readers), which may affect the stability, splicing, and/or translation of target mRNAs. Given the functional importance of the m6A modification machinery in normal bioprocesses, it is not surprising that evidence is emerging that dysregulation of m6A modification and the associated proteins also contributes to the initiation, progression, and drug response of cancers. In this review, we focus on recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated m6A modification and the associated machinery in the pathogenesis and drug response of various types of cancers. In addition, we also discuss possible therapeutic interventions against the dysregulated m6A machinery to treat cancers.

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Conflict of interest statement

We have a patent filed based on our R-2HG/FTO work (to J.C. and R.S.). The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Summary of m6A modification machinery. The m6A methyltransferase complex composed of METTL13, METTL14 and WTAP, probably also of VIRMA and RBM15, serves as m6A “writer”, demethylases (e.g., FTO and ALKBH5) serve as m6A “erasers”, and a set of m6A-binding proteins (e.g., YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, METTL3 and eIF3) serve as m6A “readers” that determine the fate of target m6A-modified mRNA transcripts
Fig. 2
Fig. 2
FTO plays a critical oncogenic role in cancer as an m6A eraser and its function can be suppressed by R-2HG. a FTO functions as an oncogenic m6A demethylase in acute myeloid leukemia. b R-2HG targets the FTO/m6A/MYC/CEBPA axis and displays anti-tumor effects in leukemia and brain tumor
Fig. 3
Fig. 3
ALKBH5 plays an oncogenic role in brain tumor and breast cancer. a ALKBH5 enhances self-renewal and proliferation of GSCs and promotes tumorigenesis through regulating expression of FOXM1 with the aid of FOXM1-AS. b HIF-induced ALKBH5 expression mediates the upregulation of pluripotency factor expression and the enrichment/specification of BCSCs in the hypoxic environment
Fig. 4
Fig. 4
METTL14 and METTL3 play oncogenic roles in leukemia. a METTL14 plays an essential oncogenic role in AML development and maintenance through regulating expression of critical targets (e.g., MYB and MYC) via an m6A-dependent mechanism. b METTL3 promotes AML cell proliferation and inhibits myeloid differentiation likely through promoting translation of its potential mRNA targets (e.g., MYC, and BCL2). c METTL3 is recruited to TSSs of target genes by CEBPZ, and its potential direct targets are SP1 and SP2, which regulate expression of MYC
Fig. 5
Fig. 5
METTL3 plays an oncogenic role in lung cancer. METTL3 enhances the growth, survival, and invasion of lung cancer cells through promoting translation of target mRNA transcripts (e.g., EGFR and TAZ)
Fig. 6
Fig. 6
IGF2BP1/2/3 proteins play oncogenic roles in cancers. IGF2BP1/2/3 proteins promote proliferation, migration, and invasion of cancer cells through post-transcriptionally regulating the stability and translation of key target mRNAs (e.g., MYC)
Fig. 7
Fig. 7
Model of YTHDF2- and IGF2BP1/2/3-mediated m6A-dependent post-transcriptional regulation of MYC expression. IGF2BP1/2/3 proteins preferentially bind to m6A sites in the 3′ end region of MYC and enhance RNA stability and promote RNA translation; in contrast, YTHDF2 protein preferentially binds to m6A sites in the 5′ end and middle regions of MYC and promotes RNA decay (based on Su et al., unpublished data)
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