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

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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Data availability

The next-generation sequencing data haves been deposited into Gene Expression Omnibus (GEO) under accession GSE97831.

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Acknowledgements

We thank Marla Weetall, John Baird, Art Branstrom and PTC Therapeutics for providing PTC596 and valuable inputs. We thank The University of Texas MD Anderson Cancer Center Science Park Next-Generation Sequencing (NGS) Facility for assistance with next-generation sequencing, and the Houston Methodist Comparative Medicine core facility, Jenny Chang, Anthony Kozielski, and Wei Qian for assistance with in vivo work. We thank Johnique Atkins for comments and editing this manuscript.

Funding

This work is supported, in part, by grants from Houston Methodist Research Institute, Prostate Cancer Foundation (13YOUN007 to QC), U.S. Department of Defense (W81XWH-15-1-0639 and W81XWH-17-1-0357 to QC), American Cancer Society (Research Scholar Grant RSG-15-192-01-TBE to QC), and NIH/NCI (R01CA208257 to QC); KC is supported in part by grants from NIH/NIGMS (R01GM125632 to KC) and NIH/NHLBI (R01HL133254 to KC); JY is supported by NIH/NCI (R01CA172384), US Department of Defense (W81XWH-17-1-0405, W81XWH-17-1-0362, and W81XWH-17-1-0578). XD is supported by the Canadian Institute of Health Research (#MOP-137007) and TFRI New Frontier Grant #1062. WZ is supported by the National Natural Science Foundation of China (81572766,81972651 and 31771630), Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029), and Natural Science Foundation of Guangdong Province (2017A030312009); CL is supported by the China Scholarship Council (201706370147). TD is supported by National Natural Science Foundation of China (81770868 and 91742103), and Innovation-driven Project of Central South University (2017CX011). The University of Texas MD Anderson Cancer Center Science Park Next-Generation Sequencing (NGS) Facility is supported by CPRIT grants RP120348 and RP170002.

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Correspondence to Kaifu Chen or Qi Cao.

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Zhu, S., Zhao, D., Li, C. et al. BMI1 is directly regulated by androgen receptor to promote castration-resistance in prostate cancer. Oncogene 39, 17–29 (2020). https://doi.org/10.1038/s41388-019-0966-4

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