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 REGγ, a proteasome activator, in mice significantly attenuates DEN-induced liver tumor formation. Ablation of REGγ 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 REGγ in HCC tumor regions contribute to reduced expression of PP2Ac, leading to accumulation of phosphorylated PRAS40 and mTORC1-mediated activation of HIF1α. Interestingly, mTORC1 enhances REGγ activity in HCC, forming a positive feedback regulatory loop. In conclusion, our study identifies REGγ-PP2Ac-PRAS40 axis as a new layer in regulating mTORC1 activity and downstream glycolytic alterations during HCC development, highlighting the REGγ-proteasome as a potential target for personalized HCC therapy.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (31730017, 31670882, 81672883), the Science and Technology Commission of Shanghai Municipality (19JC1411900, 16ZR1410000, 16QA1401500). We thank Dr. Wei Liu from Zhejiang University for providing TSC2−/− cell line. We also thank the ECNU Multifunctional Platform for Innovation (011) for keeping and raising mice.
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X.T.L., B.H.Z., J.B.L., and L.F.Y. designed research. L.F.Y. and Y.X. performed the molecular and cell biology, metabolic, data analysis and animal experiments, respectively. X.L.M., T.Y.M., and X.Q.M. were involved in the molecular and cell biology study. H.Y.Z., T.Z.W., W.S.S., and H.B.W. contributed to the animal work. B.Y. contributed to metabolomics analysis. J.R.X., J.J.L., and C.G. provided clinical samples. L.L. and P.Z. contributed to material support. X.T.L., B.H.Z., R.M., and L.F.Y. wrote the paper.
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Yao, L., Xuan, Y., Zhang, H. et al. Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma. Oncogene 40, 677–692 (2021). https://doi.org/10.1038/s41388-020-01558-8
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DOI: https://doi.org/10.1038/s41388-020-01558-8
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