BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1

Sen Zhu, Dongyu Zhao, Lin Yan, Weihua Jiang, Jung-Sun Kim, Bingnan Gu, Qipeng Liu, Rui Wang, Bo Xia, Jonathan C. Zhao, Gang Song, Wenyi Mi, Rong-Fu Wang, Xiaobing Shi, Hung-Ming Lam, Xuesen Dong, Jindan Yu, Kaifu Chen () and Qi Cao ()
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Sen Zhu: Houston Methodist Research Institute
Dongyu Zhao: Houston Methodist Research Institute
Lin Yan: Houston Methodist Research Institute
Weihua Jiang: Houston Methodist Research Institute
Jung-Sun Kim: Houston Methodist Research Institute
Bingnan Gu: Houston Methodist Research Institute
Qipeng Liu: Houston Methodist Research Institute
Rui Wang: Houston Methodist Research Institute
Bo Xia: Houston Methodist Research Institute
Jonathan C. Zhao: Northwestern University Feinberg School of Medicine
Gang Song: Peking University
Wenyi Mi: The University of Texas MD Anderson Cancer Center
Rong-Fu Wang: Houston Methodist Research Institute
Xiaobing Shi: The University of Texas MD Anderson Cancer Center
Hung-Ming Lam: University of Washington
Xuesen Dong: Vancouver Prostate Centre, Vancouver General Hospital
Jindan Yu: Northwestern University Feinberg School of Medicine
Kaifu Chen: Houston Methodist Research Institute
Qi Cao: Houston Methodist Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract BMI1, a polycomb group (PcG) protein, plays a critical role in epigenetic regulation of cell differentiation and proliferation, and cancer stem cell self-renewal. BMI1 is upregulated in multiple types of cancer, including prostate cancer. As a key component of polycomb repressive complex 1 (PRC1), BMI1 exerts its oncogenic functions by enhancing the enzymatic activities of RING1B to ubiquitinate histone H2A at lysine 119 and repress gene transcription. Here, we report a PRC1-independent role of BMI1 that is critical for castration-resistant prostate cancer (CRPC) progression. BMI1 binds the androgen receptor (AR) and prevents MDM2-mediated AR protein degradation, resulting in sustained AR signaling in prostate cancer cells. More importantly, we demonstrate that targeting BMI1 effectively inhibits tumor growth of xenografts that have developed resistance to surgical castration and enzalutamide treatment. These results suggest that blocking BMI1 alone or in combination with anti-AR therapy can be more efficient to suppress prostate tumor growth.

Date: 2018
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DOI: 10.1038/s41467-018-02863-3

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