RNF115 deficiency upregulates autophagy and inhibits hepatocellular carcinoma growth

Abstract E3 ubiquitin ligase Ring finger protein 115 (RNF115), also known as Breast cancer-associated gene 2 (BCA2) has been linked with the proliferation, migration, and invasion of breast cancer. Our study demonstrated that RNF115 is a negative regulator of autophagy in hepatoma cells. Inactivation of RNF115 can promote autophagosome formation, the fusion of autophagosomes with lysosomes, and the degradation of autophagic substrate. These effects may be related to the enhanced binding ability of RAB7 and HOPS complex and enhanced activity of ATG14 in RNF115-silenced cells. High levels of RNF115 were exhibited in most hepatic cancer tissues compared to that of the non-tumor liver tissues. Low levels of RNF115 were associated with significantly longer survival of patients with hepatocellular carcinoma. Furthermore, RNF115 silencing inhibited cellular growth and migration, and reduced tumorigenicity in a hepatoma cell xenograft model. In a DEN-induced hepatocellular carcinoma model, Rnf115KO mice developed fewer and smaller liver tumors than the WT littermates, indicating that RNF115-mediated autophagy is negatively correlated with the occurrence and development of hepatocellular carcinoma. These findings provide an experimental foundation for the prevention and treatment of hepatocellular carcinoma by targeting RNF115.