Interplay between m6 A epitranscriptome and epigenome in cancer: current knowledge and therapeutic perspectives

Chromatin has an extremely flexible structure that allows the fine regulation of gene expression. To orchestrate this process, small chemical modifications are dynamically added or removed on DNA, RNA, and histone substrates. Epigenetic modifications govern a plethora of key cellular functions, whose dysregulation contributes to oncogenesis. The interrelationship between (irreversible) genetic mutations and (reversible) epigenetic alterations and how this crosstalk regulates gene expression has long been a major area of interest. Marks modulating the RNA code (epitranscriptome), such as the well-studied N6 -methyladenosine (m6 A), are known to influence stability, metabolism, and life cycle of many mRNAs, including cancer-associated transcripts. Together, epigenetic and epitranscriptomic pathways therefore control the entire cellular expression profile and, eventually, cell fate. Recently, previously undescribed crosstalk between these two pathways has started to be unrevealed. For example, m6 A and its effectors cooperate with histone modifications to localize chromatin-modifying complexes to their target regions. Epigenetic marks governing the expression of m6 A factors can also be found at specific genetic loci. m6 A itself can mark noncoding RNAs (including lncRNAs, circRNAs, and miRNAs), influencing their structure, maturation, and function. These interactions affect both cell physiology and pathology. Clear evidence that dysregulation of this network plays a role in cancer has emerged, suggesting a new layer of complexity in the landscape of gene expression. Here, we summarize current knowledge on the interplay between m6 A epitranscriptome and epigenome, focusing on cancer processes. We also discuss strategies to target m6 A machinery for future therapeutic intervention. This article is protected by copyright. All rights reserved