The Critical Role of RNA m⁶A Methylation in Cancer.

Abstract

Since the identification of the first RNA demethylase and the establishment of methylated RNA immunoprecipitation-sequencing methodology 6 to 7 years ago, RNA methylation has emerged as a widespread phenomenon and a critical regulator of transcript expression. This new layer of regulation is termed "epitranscriptomics." The most prevalent RNA methylation, <i>N</i> ⁶-methyladenosine (m⁶A), occurs in approximately 25% of transcripts at the genome-wide level and is enriched around stop codons, in 5'- and 3'-untranslated regions, and within long internal exons. RNA m⁶A modification regulates RNA splicing, translocation, stability, and translation into protein. m⁶A is catalyzed by the RNA methyltransferases METTL3, METTL14, and METTL16 (writers), is removed by the demethylases FTO and ALKBH5 (erasers), and interacts with m⁶A-binding proteins, such as YTHDF1 and IGF2BP1 (readers). RNA methyltransferases, demethylases, and m⁶A-binding proteins are frequently upregulated in human cancer tissues from a variety of organ origins, increasing onco-transcript and oncoprotein expression, cancer cell proliferation, survival, tumor initiation, progression, and metastasis. Although RNA methyltransferase inhibitors are not available yet, FTO inhibitors have shown promising anticancer effects <i>in vitro</i> and in animal models of cancer. Further screening for selective and potent RNA methyltransferase, demethylase, or m⁶A-binding protein inhibitors may lead to compounds suitable for future clinical trials in cancer patients.