Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma

Abstract

Despite significant progression in the study of hepatocellular carcinoma (HCC), the role of the proteasome in regulating cross talk between mTOR signaling and glycolysis in liver cancer progression is not fully understood. Here, we demonstrate that deficiency of REG gamma, a proteasome activator, in mice significantly attenuates DEN-induced liver tumor formation. Ablation of REG gamma increases the stability of PP2Ac (protein phosphatase 2 catalytic subunit) in vitro and in vivo, which dephosphorylates PRAS40 (AKT1 substrate 1) and stabilizes the interaction between PRAS40 and Raptor to inactive mTORC1-mediated hyper-glycolytic metabolism. In the DEN-induced animal model and clinical hepato-carcinoma samples, high levels of REG gamma in HCC tumor regions contribute to reduced expression of PP2Ac, leading to accumulation of phosphorylated PRAS40 and mTORC1-mediated activation of HIF1 alpha. Interestingly, mTORC1 enhances REG gamma activity in HCC, forming a positive feedback regulatory loop. In conclusion, our study identifies REG gamma-PP2Ac-PRAS40 axis as a new layer in regulating mTORC1 activity and downstream glycolytic alterations during HCC development, highlighting the REG gamma-proteasome as a potential target for personalized HCC therapy.