Affiliation:
1. 1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Abstract
Abstract
Cyclin D1 (CCND1) is a critical regulator of cell proliferation and its overexpression has been linked to the development and progression of several malignancies. CCND1 overexpression is recognized as a major mechanism of therapy resistance in several cancers; tumors that rely on CCND1 overexpression to evade cancer therapy are extremely sensitive to its ablation. Therefore, targeting CCND1 is a promising strategy for preventing tumor progression and combating therapy resistance in cancer patients. Although CCND1 itself is not a druggable target, it can be targeted indirectly by inhibiting its regulators. CCND1 steady-state levels are tightly regulated by ubiquitin-mediated degradation, and defects in CCND1 ubiquitination are associated with increased CCND1 protein levels in cancer. Here, we uncover a novel function of ubiquitin-specific protease 27X (USP27X), a deubiquitinating enzyme (DUB), in regulating CCND1 degradation in cancer. USP27X binds to and stabilizes CCND1 in a catalytically dependent manner by negatively regulating its ubiquitination. USP27X expression levels correlate with the levels of CCND1 in several HER2 therapy–resistant breast cancer cell lines, and its ablation leads to a severe reduction of CCND1 protein levels, inhibition of tumor growth, and resensitization to targeted therapy. Together, the results presented in our study are the first to expose USP27X as a major CCND1 deubiquitinase and provide a mechanistic explanation for how this DUB fosters tumor growth.
Implications:
As a deubiquitinating enzyme, USP27X is a druggable target. Our study illuminates new avenues for therapeutic intervention in CCND1-driven cancers.
Funder
U.S. Department of Defense
National Institutes of Health
Roswell Park Alliance Foundation, Roswell Park Cancer Institute
Publisher
American Association for Cancer Research (AACR)
Subject
Cancer Research,Oncology,Molecular Biology
Cited by
5 articles.
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