Biologic roles of mRNA N6-methyladenosine (m6A) in high L-2-hydroxyglutarate renal cancer
The oncometabolite L-2-hydroxyglutarate (L-2HG) is commonly elevated in the most prevalent form of renal cancer.  Oncometabolites can alter the epigenome by disrupting the activities of enzymes that mediate both DNA and histone demethylation.  L-2HG has also been shown to inhibit the enzymatic activity of the RNA demethylases ALKBH5 and FTO.  Both enzymes demethylate the N6-methyladenosine (m6A) mark, the most prevalent RNA modification within mRNA.  We performed an integrative analysis on the role of m6A in high L-2HG renal carcinoma.  On a global level, L-2HG-induced m6A promotes reduced transcript levels consistent with the well-established role of m6A in reducing mRNA stability.  Ablation of METTL3, a key component of the m6A methyltransferase complex, led to bimodal effects on the transcriptome.  METTL3 activity promoted expression of genes related to interferon signalling.  In contrast, METTL3 suppressed the expression of genes related to cell cycle, specifically the G2-M phase, with concomitant effects on proliferation and cell cycle progression.  Furthermore, m6A is associated with splicing events including retained introns, not previously implicated in tumor cells.  Our data provide new insights into the functional role of m6A in renal cancer which have implications for both intrinsic tumor cell biology and the immune response. Overall design: RNA-seq profiling of control 786-O cell lines and METTL3 shRNA knockdown cell lines.