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.
Oncogene. 2023 Nov 29 [Epub ahead of print]
Carla Rodriguez Tirado, Choushi Wang, Xiaoling Li, Su Deng, Julisa Gonzalez, Nickolas A Johnson, Yaru Xu, Lauren A Metang, Medha Sundar Rajan, Yuqiu Yang, Yi Yin, Mia Hofstad, Ganesh V Raj, Song Zhang, Andrew Lemoff, Wei He, Jie Fan, Yunguan Wang, Tao Wang, Ping Mu
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA., Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA., Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA., Accutar Biotechnology, Inc., Wilmington, DE, USA., Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/38030789