USP11 promotes prostate cancer progression by up-regulating AR and c-Myc activity
Menée à l'aide d'une xénogreffe de cancer de la prostate sur un modèle murin, cette étude met en évidence un mécanisme par lequel la déubiquitinase USP11 favorise la progression tumorale via l'augmentation de l'activité du récepteur androgénique et du proto-oncogène c-Myc
Androgen receptor (AR) and c-Myc are the key transcription factors driving prostate cancer (PCa) progression. In this study, we identified the deubiquitinase USP11 as a key regulator for both AR and c-Myc. Our study revealed mechanisms by which USP11 up-regulates levels and activities of AR and c-Myc. We showed that USP11 plays a tumor-promoting role in aggressive PCa through its effect on AR and c-Myc. Thus, our study suggests that USP11 may be a target for potential PCa therapy. 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.