RNA Modification in Cancer

N 6 ‐methyladenosine (m 6 A), the most abundant internal modification in eukaryotic mRNAs, has been shown to play essential roles in various normal bioprocesses. We show recently that histone H3 trimethylation at Lys36 (H3K36me3) guided m 6 A deposition co‐transcriptionally. Evidence is emerging that m 6 A modification and the associated regulatory proteins also play critical roles in cancers. We have revealed the important functions of m 6 A regulatory proteins (e.g., FTO, METTL14 and IGF2BP1/2/3) in the development and drug response of cancer, especially acute myeloid leukemia (AML), and in the self‐renewal of leukemia stem cells (LSCs). We found that FTO is highly expressed in certain subtypes of AMLs including AMLs carrying t(11q23), t(15;17), NPM1 mutation, and/or FLT3‐ITD, in which FTO plays an essential oncogenic role in promoting leukemogenesis and in affecting drug response through post‐transcriptionally regulating expression of its critical target RNAs (such as ASB2 and RARA ) in an m 6 A‐dependent manner. Subsequently, we found that FTO is also a direct target of R‐2‐hydroxyglutarate (R‐2HG), which is produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes and has been reported as an oncometabolite. We show that by targeting the FTO/m 6 A/MYC‐CEBPA axis, R‐2HG exhibits a broad and intrinsic anti‐tumor effect in vitro and in vivo. We also show that METTL14 is overexpressed in AML and plays a critical role in the development and drug response of AML, and is also required for the self‐renewal of leukemia stem cells, by post‐transcriptionally regulating of expression of a set of essential oncogenes such as MYC and MYB . Very recently, we have developed highly selective and effective FTO inhibitor compounds that shows potent therapeutic effects in treating human AML and solid tumors in preclinical animal models, demonstrating that as an mRNA demethylase, FTO is a druggable target for cancer treatment. Moreover, we found that FTO and the associated m 6 A epitranscriptomics also plays a critical role in aerobic glycolysis (i.e., the Warburg effect) in leukemia cells. Collectively, our studies highlight the critical roles and therapeutic implication of m 6 A modification and its regulatory proteins in cancers.