The Critical Role of RNA m6A Methylation in Cancer

Abstract

Since the identification of the first RNA demethylase and the establishment of methylated RNA immunoprecipitationsequencing 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, N 6-methyladenosine (m 6 A), occurs in approximately 25% of transcripts at the genome-wide level and is enriched around stop codons, in 5 0-and 3 0-untranslated regions, and within long internal exons. RNA m 6 A modification regulates RNA splicing, translocation, stability, and translation into protein. m 6 A is catalyzed by the RNA methyltransferases METTL3, METTL14, and METTL16 (writers), is removed by the demethylases FTO and ALKBH5 (erasers), and interacts with m 6 A-binding proteins, such as YTHDF1 and IGF2BP1 (readers). RNA methyltransferases, demethylases, and m 6 Abinding proteins are frequently upregulated in human cancer tissues from a variety of organ origins, increasing oncotranscript 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 in vitro and in animal models of cancer. Further screening for selective and potent RNA methyltransferase, demethylase, or m 6 A-binding protein inhibitors may lead to compounds suitable for future clinical trials in cancer patients.

M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

“…Recent years have witnessed remarkable advancements of m 6 A modification in regulating all stages of the RNA life cycle. The deposition of m 6 A is encoded by "writers" that catalyze m 6 A formation (such as METTL3, METTL14, and WTAP), "erasers" that selectively remove the m 6 A code (such as FTO and ALKBH5), and "readers" that decode m 6 A methylation (such as YTH domain proteins and IGF2BP) [42]. m 6 A has been demonstrated to affect the targeted mRNA or miRNA and participate in the progression of various cancers [43].…”

Functions of N6-methyladenosine and its role in cancer

“…Research aimed at uncovering the mechanism has shown that m6A serves as a regulator in cancer [156,157].…”

Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

“…In the last few years, several studies have placed RNA modifications in the forefront of cancer research [36,38,64,66,77], mostly focused on the machinery responsible for writing and erasing m6A modifications. For many years, FTO was thought to be of special interest due to its association with obesity [78].…”

“…However, this is now thought to be incorrect, as later studies showed that FTO is in fact an eraser of N6,2'O-methyladenosine (m6Am), which is much less abundant in mRNAs [28,80]. Similarly, FTO has been proposed to constitute a promising target for antitumor therapies [38,81,82]. While FTO has been shown to play an important role in leukaemia [81], it is possible that additional RMPs such as HENMT1, which is drastically dysregulated in this cancer type, might constitute a better drug target to inhibit leukemogenesis (Figure 4).…”