2. Academic Validation
  3. Acetylation-dependent deubiquitinase USP26 stabilizes BAG3 to promote breast cancer progression

Acetylation-dependent deubiquitinase USP26 stabilizes BAG3 to promote breast cancer progression

  • Cancer Lett. 2024 Jun 14:597:217005. doi: 10.1016/j.canlet.2024.217005.
Jiazhou Liu 1,  Mo Zhai 2,  Yanyu Chen 3,  Yuxian Wei 4,  Fan Li 4,  Yuru Chen 1,  Bixia Duan 3,  Lei Xing 4,  Huimin Du 5,  Min Jiang 6,  Hongzhong Li 7,  Guosheng Ren 8
Affiliations

Affiliations

  • 1 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Orthopedics, Qijiang Hospital of the First Affiliated Hospital of Chongqing Medical University, Qijiang, Chongqing, 400016, China.
  • 3 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 5 Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 6 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 7 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: lihongzhong@cqmu.edu.cn.
  • 8 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. Electronic address: rengs726@126.com.
PMID: 38880224 DOI: 10.1016/j.canlet.2024.217005
Abstract

Deubiquitylases (DUBs) have emerged as promising targets for Cancer therapy due to their role in stabilizing substrate proteins within the ubiquitin machinery. Here, we identified Ubiquitin-Specific Protease 26 (USP26) as an oncogene via screening prognostic DUBs in breast Cancer. Through in vitro and in vivo experiments, we found that depletion of USP26 inhibited breast Cancer cell proliferation and invasion, and suppressed tumor growth and metastasis in nude mice. Further investigation identified co-chaperone Bcl-2-associated athanogene 3 (BAG3) as the direct substrate of USP26, and ectopic expression of BAG3 partially reversed antitumor effect induced by USP26 knockdown. Mechanistically, the lysine acetyltransferase TIP60 targeted USP26 at K134 for acetylation, which enhanced USP26 binding affinity to BAG3, leading to BAG3 deubiquitination and increased protein stability. Importantly, we employed a structure-based virtual screening and discovered a drug-like molecule called 5813669 that targets USP26, destabilizing BAG3 and effectively mitigating tumor growth and metastasis in vivo. Clinically, high expression levels of USP26 were correlated with elevated BAG3 levels and poor prognosis in breast Cancer patients. Overall, our findings highlight the critical role of USP26 in BAG3 protein stabilization and provide a promising therapeutic target for breast Cancer.

Keywords

Acetylation; Breast cancer; Deubiquitinase; USP26; Ubiquitination.

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