USP11 promotes prostate cancer progression by up- regulating AR and c- Myc activity

• 成果类型: Article
• 署名作者: Pornour, Majid; Jeon, Hee - Young; Ryu, Hyunju; Khadka, Sudeep; Xu, Rui; Chen, Hegang; Hussain, Arif; Lam, Hung - Ming; Zhuang, Zhihao; Oo, Htoo Zarni; Gleave, Martin; Dong, Xuesen; Wang, Qianben; Barbieri, Christopher; Qi, Jianfei
• 署名单位: University System of Maryland; University of Maryland Baltimore; University System of Maryland; University of Maryland Baltimore; University of Maryland Center for Environmental Science; Institute of Marine & Environmental Technology; University System of Maryland; University of Maryland Baltimore; US Department of Veterans Affairs; Veterans Health Administration (VHA); Baltimore VA Medical Center; University of Washington; University of Washington Seattle; University of Delaware; University of British Columbia; Duke University; Duke University; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8838
• DOI: 10.1073/pnas.2403331121
• 发表日期: 2024-07-30
• 关键词: chemotherapy

摘要

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.