2. Academic Validation
  3. BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer

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

  • Oncogene. 2020 Jan;39(1):17-29. doi: 10.1038/s41388-019-0966-4.
Sen Zhu  # 1,  Dongyu Zhao  # 2 3,  Chao Li  # 1 4 5,  Qiaqia Li 1 4 6,  Weihua Jiang 1,  Qipeng Liu 1 6,  Rui Wang 1,  Ladan Fazli 7 8,  Yinan Li 7 8,  Lili Zhang 1,  Yang Yi 1 4,  Qingshu Meng 1 4,  Wanyi Wang 9,  Guangyu Wang 2 3,  Min Zhang 3 10,  Xiongbing Zu 5,  Wei Zhao 11,  Tuo Deng 12,  Jindan Yu 13 14,  Xuesen Dong 7 8,  Kaifu Chen 15 16,  Qi Cao 17 18 19 20
Affiliations

Affiliations

  • 1 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA.
  • 2 Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, TX, 77030, USA.
  • 3 Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA.
  • 4 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 5 Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, China.
  • 6 Xiangya School of Medicine, Central South University, Changsha, 410008, China.
  • 7 Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada.
  • 8 Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
  • 9 Center for Research Design & Analysis, Office of Research and Sponsored Programs, Texas Woman's University, Houston, TX, 77030, USA.
  • 10 Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
  • 11 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 12 Department of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, 410011, China.
  • 13 Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 14 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 15 Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, TX, 77030, USA. kchen2@houstonmethodist.org.
  • 16 Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. kchen2@houstonmethodist.org.
  • 17 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA. qi.cao@northwestern.edu.
  • 18 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. qi.cao@northwestern.edu.
  • 19 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. qi.cao@northwestern.edu.
  • 20 Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, 77030, USA. qi.cao@northwestern.edu.
  • # Contributed equally.
PMID: 31462713 DOI: 10.1038/s41388-019-0966-4
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.

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