USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling

Mengru Ma, Lian Yi, Yifei Pei, Qimin Zhang, Chao Tong, Manyu Zhao, Yuanhong Chen, Jinghan Zhu, Wanguang Zhang, Fan Yao, Pengyuan Yang and Peijing Zhang ()
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Mengru Ma: Huazhong University of Science and Technology
Lian Yi: Huazhong University of Science and Technology
Yifei Pei: Huazhong University of Science and Technology
Qimin Zhang: University of Electronic Science and Technology of China
Chao Tong: Huazhong University of Science and Technology
Manyu Zhao: Huazhong University of Science and Technology
Yuanhong Chen: Huazhong University of Science and Technology
Jinghan Zhu: Huazhong University of Science and Technology
Wanguang Zhang: Huazhong University of Science and Technology
Fan Yao: Huazhong Agricultural University
Pengyuan Yang: Chinese Academy of Sciences
Peijing Zhang: University of Electronic Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52201-z

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