CircFTO, a c-Myc induced circRNA, sustains cell growth under Serine and Glycine deprivation

Metabolic reprogramming is recognized as a hallmark of cancer and plays a pivotal role in sustaining cell growth under metabolic stress. However, the precise mechanisms are not completely understood. Here we dissect how circFTO, a circular RNA (circRNA), reinforces the serine biosynthesis pathway (SSP) through facilitating the expression of c-Myc. We found that circFTO expression was frequently overexpressed in hepatocellular carcinoma (HCC)-derived cell lines and tissues compared to their normal hepatic cell counterparts. In the context of HCC, we showed circFTO acts as ligand to bind and stabilize IGF2BPs, then elevated c-Myc expression through prolonging c-Myc mRNA half-life. In response to SG deprivation (Serine&Glycine deprivation), circFTO was transcriptionally induced by c-Myc, thus formed a circFTO-c-Myc positive feedback loop. In consequence, SSP components including PHGDH, PSAT1, PSPH, SHMT1 and SHMT2 are upregulated though the circFTO-c-Myc feedback loop. Intriguingly, some evidences showed the circFTO-c-Myc feedback loop is able to shift glucose metabolic flux towards SSP. Manipulating circFTO elicited robust effects on SSP associated genes with marked changes in HCC growth in vitro and in xenograft models under both normal and SG deprivation condition, indicative of the significant contribution of circFTO to tumorigenic phenotypes. Moreover, circFTO level is positively related to c-Myc expression in hepatocellular carcinoma tissues. Together, this work identifies circFTO as an integral element of SSP-regulated metabolic reprogramming under SG deprivation and implicitly highlights the potential of targeting circFTO to selectively counter the cancers.