BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer

• Published in: Oncogene 2020-01, Vol.39 (1), p.17-29
• Main Authors: Zhu, Sen, Zhao, Dongyu, Li, Chao, Li, Qiaqia, Jiang, Weihua, Liu, Qipeng, Wang, Rui, Fazli, Ladan, Li, Yinan, Zhang, Lili, Yi, Yang, Meng, Qingshu, Wang, Wanyi, Wang, Guangyu, Zhang, Min, Zu, Xiongbing, Zhao, Wei, Deng, Tuo, Yu, Jindan, Dong, Xuesen, Chen, Kaifu, Cao, Qi
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 38/90; 631/208/200; 631/67/589/466; 82/80; Analysis; Androgen receptors; Androgens; Animals; Apoptosis; B-cell lymphoma; Binding sites; Binding Sites - genetics; Cancer; Castration; Cell Biology; Cell proliferation; Cell Proliferation - drug effects; Development and progression; Dihydrotestosterone; Dihydrotestosterone - administration & dosage; DNA-Binding Proteins - genetics; Enhancer Elements, Genetic - genetics; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genome editing; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Mesenchyme; Mice; mRNA; Non-Hodgkin's lymphomas; Oncology; Polycomb Repressive Complex 1 - genetics; Promoter Regions, Genetic - genetics; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - genetics; RNA; RNA, Messenger - genetics; Stem cells; Tissue Array Analysis; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0966-4

B lymphoma Mo-MLV insertion region 1 (BMI1) has been reported to be an oncoprotein. BMI1 represses tumor suppressors to promote cell proliferation, epithelial-mesenchymal transition (EMT), and cancer progression. Although it is known that the expression of BMI1 is increased in many cancer types, the mechanism of BMI1 upregulation is not yet clear. We performed integrative analysis for 3 sets of prostate cancer (PCa) genomic data, and found that BMI1 and androgen receptor (AR) were positively correlated, suggesting that AR might regulate BMI1. Next, we showed that dihydrotestosterone (DHT) upregulated both mRNA and protein levels of BMI1 and that BMI1 was increased in castration-resistant prostate cancer (CRPC) from both human patients and a mouse xenograph model. We further identified an AR binding site in the promoter/enhancer region of BMI1, and confirmed BMI1 as the direct target of AR using gene-editing technology. We also demonstrated that high expression of BMI1 is critical for the development of castration-resistance. Our data also suggest that BMI1-specific inhibitors could be an effective treatment of CRPC.