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.

Details

Title
BMI1 regulates androgen receptor in prostate cancer independently of the polycomb repressive complex 1
Author
Zhu, Sen 1 ; Zhao, Dongyu 2 ; Lin, Yan 3 ; Jiang, Weihua 1 ; Jung-Sun, Kim 1 ; Gu, Bingnan 1 ; Liu, Qipeng 3 ; Wang, Rui 1 ; Xia, Bo 2 ; Zhao, Jonathan C 4 ; Song, Gang 5 ; Mi, Wenyi 6   VIAFID ORCID Logo  ; Rong-Fu, Wang 7 ; Shi, Xiaobing 6   VIAFID ORCID Logo  ; Hung-Ming, Lam 8 ; Dong, Xuesen 9 ; Yu, Jindan 10 ; Chen, Kaifu 2 ; Cao, Qi 11   VIAFID ORCID Logo 

1  Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA 
2  Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA; Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA 
3  Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA; Xiangya School of Medicine, Central South University, Changsha, Hunan, China 
4  Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 
5  Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, China 
6  Department of Epigenetics and Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 
7  Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA 
8  Department of Urology, University of Washington, Seattle, WA, USA; 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), China 
9  Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada 
10  Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 
11  Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA 
Pages
1-13
Publication year
2018
Publication date
Feb 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-02863-3
ProQuest document ID
1994395329
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.