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

Hengyou Weng,Xiaolan Deng,Zejuan Li,Jianjun Chen,Huilin Huang,Rui Su

doi:10.1038/s41422-018-0034-6

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.

Highlights

It is well known that gene expression and cell growth/division are under sophisticated controls through genetic and epigenetic regulations
fat mass and obesity-associated protein (FTO) functions as an oncoprotein in both leukemia and GBM55,60 and ALKBH5 plays an oncogenic role in both breast cancer and GBM.[72,73]
While the oncogenic roles of METTL3 and METTL14 in acute myeloid leukemia (AML) have been confirmed by different groups,[75,82,83] their reported functions in brain and liver cancers are controversial.[60,85,86,87]

Summary

REVIEW ARTICLE OPEN

Xiaolan Deng[1,2,3], Rui Su1,3, Hengyou Weng[1,3], Huilin Huang[1,3], Zejuan Li4 and Jianjun Chen 1,3. 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 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 contributes to the initiation, progression, and drug response of cancers. 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. We discuss possible therapeutic interventions against the dysregulated m6A machinery to treat cancers

INTRODUCTION

CONCLUSIONS AND PERSPECTIVES

Functional mechanism

Findings

516 REFERENCES