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.
Highlights
Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients
We show that increased AR expression markedly enhances androgen-mediated transcriptional repression, and that this repression is largely independent of AR binding to chromatin and is associated with coactivator redistribution
Attenuated by DHT, while interaction with sites in PVT1 were retained or enhanced. These findings were further confirmed by chromosome conformation capture (3C) (Fig. 6c). These results show that DHT-mediated repression of MYC expression is associated with a robust architectural change in 8q24 topologically associated domain (TAD), with a marked decrease in MYC promoter interaction with the PCAT1 SE, which may be partially compensated by an increased interaction with the PVT1 region
Summary
Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. 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 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. A subset of these relapsed tumors appear to be ARindependent, but the majority have persistently high levels of AR expression and activity One mechanism driving this increased AR expression is amplification of the AR gene and an upstream AR enhancer, which occurs in the majority of cases[1,2,3]. We establish that androgen treatment represses MYC expression by disrupting the interaction between the prostate-specific MYC super-enhancer within the PCAT1 gene and the MYC promoter
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