biostudies-literaturePornour MBLRD VAHHS | NIH | National Cancer InstituteU.S. Department of Defense (DOD)U.S. Department of DefenseNCI NIH HHSHHS | NIH | National Cancer Institute (NCI)NIGMS NIH HHSe2403331121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11295044biostudies-literatureUnknown121(31)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 AmericaUSP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.PMC11295044R01 GM129468R01 CA244667PC210437P30 CA134274I01 BX000545R01CA244667Hussain AJeon HYQi JDong XXu RGleave MRyu HChen HPornour MZhuang ZKhadka SBarbieri CLam HMWang QOo HZfalseUSP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity.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.2024-01-01T00:00:00Z2024 Jul2025-04-04T02:09:53.34Z2025-04-04T02:09:53.34ZS-EPMC112950443905283510.1073/pnas.2403331121