The roles and implications of RNA m6A modification in cancer

• Published in: Nature reviews. Clinical oncology 2023-08, Vol.20 (8), p.507-526
• Main Authors: Deng, Xiaolan, Qing, Ying, Horne, David, Huang, Huilin, Chen, Jianjun
• Format: Article
• Language: English
• Subjects: 631/154/555; 692/308/575; 692/420/755; 692/53/2422; 692/699/67/1857; Biomarkers; Cancer; Cancer therapies; Cell self-renewal; Medicine; Medicine & Public Health; Metastases; Molecular modelling; mRNA; N6-methyladenosine; Oncology; Phenotypes; Review Article; RNA modification; Tumor microenvironment; Tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-023-00774-x

N 6 -Methyladenosine (m 6 A), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of RNA m 6 A modification and its associated machinery, including writers, erasers and readers, is frequently observed in various cancer types, and the dysregulation profiles might serve as diagnostic, prognostic and/or predictive biomarkers. Dysregulated m 6 A modifiers have been shown to function as oncoproteins or tumour suppressors with essential roles in cancer initiation, progression, metastasis, metabolism, therapy resistance and immune evasion as well as in cancer stem cell self-renewal and the tumour microenvironment, highlighting the therapeutic potential of targeting the dysregulated m 6 A machinery for cancer treatment. In this Review, we discuss the mechanisms by which m 6 A modifiers determine the fate of target RNAs and thereby influence protein expression, molecular pathways and cell phenotypes. We also describe the state-of-the-art methodologies for mapping global m 6 A epitranscriptomes in cancer. We further summarize discoveries regarding the dysregulation of m 6 A modifiers and modifications in cancer, their pathological roles, and the underlying molecular mechanisms. Finally, we discuss m 6 A-related prognostic and predictive molecular biomarkers in cancer as well as the development of small-molecule inhibitors targeting oncogenic m 6 A modifiers and their activity in preclinical models. Dysregulation of N 6 -methyladenosine (m 6 A), the most prevalent internal modification in eukaryotic mRNA, is common in various cancer types. The authors of this Review provide an overview of the mechanisms of m 6 A-dependent RNA regulation, summarize current knowledge of their pathological effects and potential utility as biomarkers in cancer, and describe ongoing efforts to develop small-molecule inhibitors of oncogenic m 6 A modifiers. Key points Epitranscriptomics relates to the post-transcriptional regulation of RNAs involving >170 chemical modifications, constituting one of several regulatory layers controlling gene expression. N 6 -Methyladenosine (m 6 A) is a major epitranscriptomic modification that contributes to the dynamic regulation of every biological process. m 6 A marks are reversibly added by writers and removed by erasers, and are recognized by readers; this machinery modulates RNA splicing, nuclear export, stability and translation to determine the fate of RNAs a