Despite recent advances in systemic treatments for hepatocellular carcinoma (HCC), patients with Hepatitis B Virus (HBV)-induced HCC continue to have a poor prognosis. This study explores the role of deubiquitinases in HBV-positive HCC and seeks to uncover potential new therapeutic targets. It establishes a direct link between HBV infection, deubiquitinase activation, and HCC development, highlighting USP26 as a crucial factor. The findings suggest that USP26 could be a valuable target for developing new treatments.1
The screening showed that when USP26 is lacking, HBV-positive HCC cells grow less effectively. Studies using mice with a Usp26 knockout confirmed that USP26 is essential for HCC tumor growth.
USP26 (Ubiquitin-Specific Protease 26) encodes a deubiquitinating enzyme (DUB) that belongs to the ubiquitin-specific processing (UBP) family. This gene is mainly active in the testis and is linked to conditions like Sertoli cell-only syndrome and male infertility.2
Relationship Between HBV and HCC in This Study
- The study examines how HBV infection contributes to the development of HCC by activating deubiquitinases, specifically USP26.
- It identifies that the HBV protein HBx activates USP26 by binding to its promoter, leading to the stabilization of SIRT1 and promoting HCC tumorigenesis.
- The study finds that higher USP26 levels in HBV-positive HCC patients are associated with increased SIRT1 levels and poorer prognosis, highlighting USP26 as a key factor in HBV-related HCC.
“In this study, we identified USP26 as an oncogenic driver of HCC and the mechanism underlying the association between HBV infection and HCC occurrence: in response to HBV infection, USP26 is transcriptionally activated and consequently recruits the HBV-encoded X protein HBx to interact with SIRT1, which synergistically deubiquitinates and stabilizes SIRT1.”1
The HBV protein HBx (Hepatitis B Virus X Protein) was found to activate USP26 production by binding to its promoter. USP26, which is normally found only in the testis, works with SIRT1 (Sirtuin 1) to keep SIRT1 stable through deubiquitination. This interaction boosts cell growth and prevents cell death, which speeds up HCC development. In patients with HBV-positive HCC, higher levels of USP26 are linked to increased SIRT1 levels and worse outcomes.
They screened a sgRNA library targeting human deubiquitinases to identify factors affecting HBV-positive HCC cell proliferation. Additionally, they utilized genetically engineered murine models with Usp26 knockout to confirm the role of USP26 in HCC tumorigenesis.
“Our study uncovers that HBx plays dual roles in stabilizing the SIRT1 protein through the deubiquitinase USP26, which further clarifies how HBV infection induces HCC progression,” according to the investigators.1
The study notes limitations in using SIRT1 inhibitors like EX527. Although it was tolerated in clinical trials for Huntington’s disease, EX527 affects T-cell function and has shown variable results in cancer treatment. It may also target SIRT2 or other unknown proteins, leading to unpredictable outcomes. These factors highlight challenges in developing SIRT1 inhibitors for cancer therapy.
In conclusion, this study identifies USP26 as a key factor in HBV-induced HCC and highlights its role in tumor growth and interaction with HBx and SIRT1. USP26 could be a potential target for new treatments. However, limitations in using SIRT1 inhibitors like EX527, due to effects on T-cells and off-target interactions, suggest the need for further research.
References
Ma M, Yi, L Pei, Y. et al. USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling. Nat Commun 15, 7856 (2024). Accessed September 11, 2024. https://doi.org/10.1038/s41467-024-52201-z
USP26 ubiquitin specific peptidase 26 [ Homo sapiens (human) ]. National Library of Medicine. August 27, 2024. Accessed September 11, 2024. https://www.ncbi.nlm.nih.gov/gene/83844
