UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance.

Autor: Rodriguez Tirado C; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Wang C; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Li X; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Deng S; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Gonzalez J; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Johnson NA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Xu Y; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Metang LA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Sundar Rajan M; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Yang Y; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA., Yin Y; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Hofstad M; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Raj GV; Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA., Zhang S; Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA., Lemoff A; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA., He W; Accutar Biotechnology, Inc., Wilmington, DE, USA., Fan J; Accutar Biotechnology, Inc., Wilmington, DE, USA., Wang Y; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Wang T; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA., Mu P; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA. Ping.Mu@UTSouthwestern.edu.; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA. Ping.Mu@UTSouthwestern.edu.; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA. Ping.Mu@UTSouthwestern.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Jan; Vol. 43 (4), pp. 265-280. Date of Electronic Publication: 2023 Nov 29.
DOI: 10.1038/s41388-023-02890-5
Abstrakt: Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5-15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.
(© 2023. The Author(s).)
Databáze: MEDLINE
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