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

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

Zhu S1, Zhao D2,3, Yan L1,4, Jiang W1, Kim JS1, Gu B1, Liu Q1,4, Wang R1, Xia B2,3, Zhao JC5, Song G6, Mi W7, Wang RF1,8, Shi X7, Lam HM9,10, Dong X11,12, Yu J5,13, Chen K14,15, Cao Q16,17,18.

Author information

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. kchen2@houstonmethodist.org.
15
Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. kchen2@houstonmethodist.org.
16
Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA. qcao@houstonmethodist.org.
17
Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. qcao@houstonmethodist.org.
18
Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, 77030, USA. qcao@houstonmethodist.org.

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.

PMID:
29402932
PMCID:
PMC5799368
DOI:
10.1038/s41467-018-02863-3
[Indexed for MEDLINE]
Free PMC Article

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