Aberrant RNA m(6)A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities

Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m(6)A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m(6)A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m(6)A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m(6)A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m(6)A machinery are integrated with a timeline of developing m(6)A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m(6)A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m(6)A homeostasis, and how m(6)A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics. [Figure: see text]