Androgen receptor and MYC equilibration centralizes on developmental super-enhancer.

Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. Here, we show that this repression is independent of AR chromatin binding and driven by coactivator redistribution, and through chromatin conformation capture methods show disruption of the interaction between the MYC super-enhancer within the PCAT1 gene and the MYC promoter. Conversely, androgen deprivation in vitro and in vivo increases MYC expression. In parallel, global AR activity is suppressed by MYC overexpression, consistent with coactivator redistribution. These suppressive effects of AR and MYC are mitigated at shared AR/MYC binding sites, which also have markedly higher levels of H3K27 acetylation, indicating enrichment for functional enhancers. These findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.

Nature communications. 2021 Dec 15*** epublish ***

Haiyang Guo, Yiming Wu, Mannan Nouri, Sandor Spisak, Joshua W Russo, Adam G Sowalsky, Mark M Pomerantz, Zhao Wei, Keegan Korthauer, Ji-Heui Seo, Liyang Wang, Seiji Arai, Matthew L Freedman, Housheng Hansen He, Shaoyong Chen, Steven P Balk

Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033,, Shandong, China., Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA., Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China., Department of Statistics, University of British Columbia, Vancouver, BC, Canada., Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. ., Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA. ., Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA. .

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