M6A demethylase fat mass and obesity-associated protein regulates cisplatin resistance of gastric cancer by modulating autophagy activation through ULK1

Abstract

Drug resistance is an important factor for treatment failure of gastric cancer. N6-methyladenosine (m6A) is the predominant mRNA internal modification in eukaryotes. The roles of m6A modification in drug resistance of gastric cancer remains unclear. In the present study, the m6A methylated RNA level was significantly decreased while the expression of m6A demethylase fat mass and obesity-associated protein (FTO) was obviously elevated in cisplatin-resistant (SGC-7901/DDP) gastric cancer cells. Knockdown of FTO reversed cisplatin resistance of SGC-7901/DDP cells both in vitro and in vivo, which was attributed to the inhibition of Unc-51-like kinase 1 (ULK1)-mediated autophagy. Mechanistically, ULK1 expression was regulated in an FTO-m6A-dependent and YTHDF2-mediated manner. Collectively, our findings indicate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer.