N6-Methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, has been extensively and increasingly studied over the past decade. Dysregulation of RNA m6A 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 m6A 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 m6A machinery for cancer treatment. In this Review, we discuss the mechanisms by which m6A 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 m6A epitranscriptomes in cancer. We further summarize discoveries regarding the dysregulation of m6A modifiers and modifications in cancer, their pathological roles, and the underlying molecular mechanisms. Finally, we discuss m6A-related prognostic and predictive molecular biomarkers in cancer as well as the development of small-molecule inhibitors targeting oncogenic m6A modifiers and their activity in preclinical models.
Epitranscriptomics relates to the post-transcriptional regulation of RNAs involving >170 chemical modifications, constituting one of several regulatory layers controlling gene expression. N6-Methyladenosine (m6A) is a major epitranscriptomic modification that contributes to the dynamic regulation of every biological process.
m6A 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 and thus ensure tight control over gene expression.
Advanced global characterization and mapping techniques that provide information on locus-specific changes in m6A modification are key to a deeper understanding of the wide-ranging roles of m6A in the regulation of gene expression.
Dysregulation of m6A modifiers (writers, erasers and readers) is common across cancer types and has essential roles in cancer initiation, progression, metastasis, metabolism, drug resistance and immune evasion as well as in the tumour microenvironment.
Aberrant expression of m6A modifiers in cancer has been associated with a poor prognosis, therapy resistance and impaired antitumour immunity, and might therefore provide biomarkers with independent predictive value for use in diagnosis, prognostication and treatment selection.
Preclinical data underscore the potential of small-molecule inhibitors of oncogenic m6A modifiers in the treatment of cancer, either alone or in combination with conventional chemotherapy or immunotherapies.
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The work of the authors is partly supported by the US National Institutes of Health (NIH) grants R01 CA271497 and R01 CA 243386 (to J.C.), and a grant from the National Natural Science Foundation of China (82173058, to H.H.). We apologize to the researchers whose work could not be cited owing to space constraints.
J.C. is a scientific advisory board member of Race Oncology. The other authors declare no competing interests.
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Deng, X., Qing, Y., Horne, D. et al. The roles and implications of RNA m6A modification in cancer. Nat Rev Clin Oncol (2023). https://doi.org/10.1038/s41571-023-00774-x