Androgen receptor and MYC equilibration centralizes on developmental super-enhancer

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 () and Steven P. Balk ()
Additional contact information
Haiyang Guo: Shandong University
Yiming Wu: Beth Israel Deaconess Medical Center and Harvard Medical School
Mannan Nouri: Beth Israel Deaconess Medical Center and Harvard Medical School
Sandor Spisak: Harvard Medical School
Joshua W. Russo: Beth Israel Deaconess Medical Center and Harvard Medical School
Adam G. Sowalsky: National Cancer Institute, National Institutes of Health
Mark M. Pomerantz: Harvard Medical School
Zhao Wei: Qilu Hospital of Shandong University
Keegan Korthauer: University of British Columbia
Ji-Heui Seo: Harvard Medical School
Liyang Wang: Beth Israel Deaconess Medical Center and Harvard Medical School
Seiji Arai: Beth Israel Deaconess Medical Center and Harvard Medical School
Matthew L. Freedman: Harvard Medical School
Housheng Hansen He: University of Toronto
Shaoyong Chen: Beth Israel Deaconess Medical Center and Harvard Medical School
Steven P. Balk: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27077-y

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