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

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

doi:10.1038/s41388-019-0966-4

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

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 DongKaifu Chen, Qi Cao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Pages (from-to)	17-29
Number of pages	13
Journal	Oncogene
Volume	39
Issue number	1
DOIs	https://doi.org/10.1038/s41388-019-0966-4
State	Published - Jan 2 2020

Funding

Funding This work is supported, in part, by grants from Houston Methodist Research Institute, Prostate Cancer Foundation (13YOUN007 to QC), U.S. Department of Defense (W81XWH-15-1-0639 and W81XWH-17-1-0357 to QC), American Cancer Society (Research Scholar Grant RSG-15-192-01-TBE to QC), and NIH/NCI (R01CA208257 to QC); KC is supported in part by grants from NIH/ NIGMS (R01GM125632 to KC) and NIH/NHLBI (R01HL133254 to KC); JY is supported by NIH/NCI (R01CA172384), US Department of Defense (W81XWH-17-1-0405, W81XWH-17-1-0362, and W81XWH-17-1-0578). XD is supported by the Canadian Institute of Health Research (#MOP-137007) and TFRI New Frontier Grant #1062. WZ is supported by the National Natural Science Foundation of China (81572766,81972651 and 31771630), Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029), and Natural Science Foundation of Guangdong Province (2017A030312009); CL is supported by the China Scholarship Council (201706370147). TD is supported by National Natural Science Foundation of China (81770868 and 91742103), and Innovation-driven Project of Central South University (2017CX011). The University of Texas MD Anderson Cancer Center Science Park Next-Generation Sequencing (NGS) Facility is supported by CPRIT grants RP120348 and RP170002.

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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.",

author = "Sen Zhu and Dongyu Zhao and Chao Li and Qiaqia Li and Weihua Jiang and Qipeng Liu and Rui Wang and Ladan Fazli and Yinan Li and Lili Zhang and Yang Yi and Qingshu Meng and Wanyi Wang and Guangyu Wang and Min Zhang and Xiongbing Zu and Wei Zhao and Tuo Deng and Jindan Yu and Xuesen Dong and Kaifu Chen and Qi Cao",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = jan,

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doi = "10.1038/s41388-019-0966-4",

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Zhu, S, Zhao, D, Li, C, Li, Q, Jiang, W, Liu, Q, Wang, R, Fazli, L, Li, Y, Zhang, L, Yi, Y , Meng, Q, Wang, W, Wang, G, Zhang, M, Zu, X, Zhao, W, Deng, T, Yu, J, Dong, X, Chen, K & Cao, Q 2020, 'BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer', Oncogene, vol. 39, no. 1, pp. 17-29. https://doi.org/10.1038/s41388-019-0966-4

TY - JOUR

T1 - BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer

AU - Zhu, Sen

AU - Zhao, Dongyu

AU - Li, Chao

AU - Li, Qiaqia

AU - Jiang, Weihua

AU - Liu, Qipeng

AU - Wang, Rui

AU - Fazli, Ladan

AU - Li, Yinan

AU - Zhang, Lili

AU - Yi, Yang

AU - Meng, Qingshu

AU - Wang, Wanyi

AU - Wang, Guangyu

AU - Zhang, Min

AU - Zu, Xiongbing

AU - Zhao, Wei

AU - Deng, Tuo

AU - Yu, Jindan

AU - Dong, Xuesen

AU - Chen, Kaifu

AU - Cao, Qi

PY - 2020/1/2

Y1 - 2020/1/2

N2 - 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.

AB - 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.

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

Abstract

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UN SDGs

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