The Emerging Roles of RNA m6A Methylation and Demethylation as Critical Regulators of Tumorigenesis, Drug Sensitivity, and Resistance

RNA N⁶ -methyladenosine (m⁶A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m⁶A is regulated by the RNA m⁶A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1-2, YTHDF1-3, IGF2BP1-3, and SND1 (readers). These RNA m⁶A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m⁶A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m⁶A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m⁶A modification protein expression or RNA m⁶A modification protein-induced resistance to cancer therapy.