Androgen receptor (AR) is a main driver for castration-resistant prostate cancer (CRPC). c-Myc is an oncogene underlying prostate tumorigenesis. Here, we find that the deubiquitinase USP11 targets both AR and c-Myc in prostate cancer (PCa). USP11 expression was up-regulated in metastatic PCa and CRPC. USP11 knockdown (KD) significantly inhibited PCa cell growth. Our RNA-seq studies revealed AR and c-Myc as the top transcription factors altered after USP11 KD. ChIP-seq analysis showed that either USP11 KD or replacement of endogenous USP11 with a catalytic-inactive USP11 mutant significantly decreased chromatin binding by AR and c-Myc. We find that USP11 employs two mechanisms to up-regulate AR and c-Myc levels: namely, deubiquitination of AR and c-Myc proteins to increase their stability and deubiquitination of H2A-K119Ub, a repressive histone mark, on promoters of AR and c-Myc genes to increase their transcription. AR and c-Myc reexpression in USP11-KD PCa cells partly rescued cell growth defects. Thus, our studies reveal a tumor-promoting role for USP11 in aggressive PCa through upregulation of AR and c-Myc activities and support USP11 as a potential target against PCa.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Jul 25 [Epub]
Majid Pornour, Hee-Young Jeon, Hyunju Ryu, Sudeep Khadka, Rui Xu, Hegang Chen, Arif Hussain, Hung-Ming Lam, Zhihao Zhuang, Htoo Zarni Oo, Martin Gleave, Xuesen Dong, Qianben Wang, Christopher Barbieri, Jianfei Qi
Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, MD 21201., Department of Epidemiology and Public Health, University of Maryland, Baltimore, MD 21201., Department of Urology, University of Washington, Seattle, WA 98195., Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada., Department of Pathology and Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710., Department of Urology, Weill Cornell Medical College, Cornell University, New York, NY 10065.