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

Nat Commun. 2018 Feb 5;9(1):500. doi: 10.1038/s41467-018-02863-3.

Sen Zhu ¹, Dongyu Zhao ² ³, Lin Yan ¹ ⁴, Weihua Jiang ¹, Jung-Sun Kim ¹, Bingnan Gu ¹, Qipeng Liu ¹ ⁴, Rui Wang ¹, Bo Xia ² ³, Jonathan C Zhao ⁵, Gang Song ⁶, Wenyi Mi ⁷, Rong-Fu Wang ¹ ⁸, Xiaobing Shi ⁷, Hung-Ming Lam ⁹ ¹⁰, Xuesen Dong ¹¹ ¹², Jindan Yu ⁵ ¹³, Kaifu Chen ¹⁴ ¹⁵, Qi Cao ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.
2 Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA.
3 Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA.
4 Xiangya School of Medicine, Central South University, Changsha, Hunan, 410008, China.
5 Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
6 Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, 100034, China.
7 Department of Epigenetics and Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
8 Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA.
9 Department of Urology, University of Washington, Seattle, WA, 98195, USA.
10 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), 999078, China.
11 Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada.
12 Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
13 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
14 Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, 77030, USA. [email protected].
15 Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. [email protected].
16 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA. [email protected].
17 Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. [email protected].
18 Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, 77030, USA. [email protected].

PMID: 29402932 DOI: 10.1038/s41467-018-02863-3

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-15888

PTC-209

99.85%, BMI-1 Inhibitor

Autophagy

Cancer

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