WDR20 prevents hepatocellular carcinoma senescence by orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc

• 成果类型: Article
• 署名作者: Jiang, Li; Qi, Xuxin; Lai, Minshan; Zhou, Jiahao; Yuan, Meng; You, Jieqiong; Liu, Qiang; Pan, Jinchang; Zhao, Luyao; Ying, Meidan; Ji, Junfang; Li, Ke; Zhang, Yan; Pan, Weiwei; He, Qiaojun; Yang, Bo; Cao, Ji
• 署名单位: Zhejiang University; Zhejiang University; Zhejiang University; Westlake University; Zhejiang University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Liangzhu Laboratory; Zhejiang University; Zhejiang University; Jiaxing University; Hangzhou City University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13000
• DOI: 10.1073/pnas.2407904121
• 发表日期: 2024-10-29
• 关键词: ubiquitin-proteasome system; cellular senescence; down-regulation; activation; proteins; reversal; receptor; p53

摘要

The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS- related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without affecting normal hepatocytes. Moreover, the downregulation of WDR20 expression induced HCC cellular senescence and suppressed tumor progression in xenograft, sleeping beauty transposon/transposase, and hydrodynamic tail vein injection- induced HCC models, and Alb-Cre+/MYC+ HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46- mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of CDKN1A. Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient- derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy.