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

Abstract

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.

• Authors: Sen Zhu, Dongyu Zhao, Chao Li, Qiaqia Li, Weihua Jiang, Qipeng Liu, Rui Wang, Ladan Fazli, Yinan Li, Lili Zhang, Yang Yi, Qingshu Meng, Wanyi Wang, Guangyu Wang, Min Zhang, Xiongbing Zu, Wei Zhao, Tuo Deng, Jindan Yu, Xuesen Dong, Kaifu Chen, Qi Cao
• Journal: Oncogene (Oncogene) Vol. 39 Issue 1 Pg. 17-29 (01 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31462713 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AR protein, human
• BMI1 protein, human
• DNA-Binding Proteins
• RNA, Messenger
• Receptors, Androgen
• Dihydrotestosterone
• Polycomb Repressive Complex 1

Topics

• Animals
• Binding Sites (genetics)
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (genetics)
• Dihydrotestosterone (administration & dosage)
• Enhancer Elements, Genetic (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Polycomb Repressive Complex 1 (genetics)
• Promoter Regions, Genetic (genetics)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• RNA, Messenger (genetics)
• Receptors, Androgen (genetics)
• Tissue Array Analysis
• Xenograft Model Antitumor Assays