Intertwined regulation between RNA m6A modification and cancer metabolism

Abstract

RNA N6-methyladenosine (m⁶A) has been identified as the most common, abundant and conserved internal modification in RNA transcripts, especially within eukaryotic messenger RNAs (mRNAs). Accumulating evidence demonstrates that RNA m⁶A modification exploits a wide range of regulatory mechanisms to control gene expression in pathophysiological processes including cancer. Metabolic reprogramming has been widely recognized as a hallmark of cancer. Cancer cells obtain metabolic adaptation through a variety of endogenous and exogenous signaling pathways to promote cell growth and survival in the microenvironment with limited nutrient supply. Recent emerging evidence reveals reciprocal regulation between the m⁶A modification and disordered metabolic events in cancer cells, adding more complexity in the cellular network of metabolic rewiring. In this review, we summarize the most recent advances of how RNA methylation affects tumor metabolism and the feedback regulation of m⁶A modification by metabolic intermediates. We aim to highlight the important connection between RNA m⁶A modification and cancer metabolism, and expect that studise of RNA m⁶A and metabolic reprogramming will lead to greater understanding of cancer pathology.

Fig. 1

The RNA m⁶A methylation of key metabolic enzymes or regulators modulates glucose, glutamine and lipid metabolism. In glucose metabolism, The METTL3/WTAP complex catalyzes the m⁶A modification in transcripts of GLUT1, HK2, ENO1 and PKM2 and promotes the mRNA stability or enhances the translation. The m⁶A reader YTHDF1 accelerates the translation of PKM2 and the m⁶A demethylase FTO promotes the mRNA stability of LDHB. METTL3 also indirectly affects metabolic enzyme expression via adding m⁶A on the APC and HDGF transcripts. In glutamine metabolism, FTO and YTHDF1 promote the mRNA stability of SLC1A5 and GLS2 respectively. YTHDF1 enhances the GLS1 translation. In lipid metabolism, METTL3 and YTHDF2 coordinate to promote the PPAPα mRNA stability. See the text for more details.

Fig. 2

Metabolite intermediates modulate the key components of the m⁶A machinery. The abundance of methyl group donor SAM, produced from one-carbon metabolism, controls the methyl transferase reaction catalyzed by METTL3. The ALKBH5 and FTO demethylase activity can be modulated by NADP(H), α-KG, R-2HG, succinate and fumarate. See the text for more details.