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.

No data was excluded from the analyses.
For each experiment, all attempts at replication were successful.
Randomization was not considered within the experimental groups tested.
The animal experiments were conducted as a blinded study by technicians and were unknowing of the origins of the cells being tested.

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LNCaP ATCC CRL-1740 VCaP ATCC CRL-2876 We utilized ATCC services following extended passages to authenticate by utilizing Short Tanden Repeat (STR) profiling. Sequences were amplified 17 STR loci plus Amelogenin using Promega's PowerPlex® 18D System. A comprehensive analysis report interprets both karyotypically normal and abnormal cell lines, includes a electropherograms supporting the allele calls at each locus, known reference profiling against the ATCC STR database and a comprehensive interpretation of results.
All cell lines were tested for mycoplasma contamination using MycoAlert™ Mycoplasma Detection Kit (LT07-118, Lonza). No mycoplasma contamination was detected in these cell lines.
No cell lines used in this study are listed in the database of commonly misidentified cell lines maintained by ICLAC.
Six-to eight-week-old male ICR/scid mice (IcrTac:ICR-Prkdc<scid>) from Taconic (Taconic Biosciences, Inc., 273 Hover Avenue, Germantown, NY 12526, USA) were used to generate PCa xenografts. The mice are housed in Allentown HEPA-filtered, individually ventilated cages with ducted HEPA exhaust and automatic watering. Irradiated food and hyperchlorinated, reverse osmosis water are provided to all cages. Rodent racks, cages, and bedding are autoclaved in double-door bulk autoclaves prior to use. The mice were injected subcutaneously with 2 million VCaP cells in 50% Matrigel. When Xenografts reached~1000 mm3, biopsies were obtained. Additional biopsies were obtained 4 d after castration, and the tumors were harvested at relapse (3 weeks).