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Abstract
Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.
The pathogenesis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains to be understood. Here the authors identify that USP26 deubiquitinase drives the progression of HBV-associated HCC via regulating the protein stability of Sirtuin 1.
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1 Huazhong University of Science and Technology, National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)
2 University of Electronic Science and Technology of China, Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China (GRID:grid.54549.39) (ISNI:0000 0004 0369 4060)
3 Huazhong University of Science and Technology, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)
4 Huazhong Agricultural University, Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Wuhan, China (GRID:grid.35155.37) (ISNI:0000 0004 1790 4137)
5 Chinese Academy of Sciences, Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)