SRA

Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the AR-targeted therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs has remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. In comparison to FOXA1, inhibition of coregulator activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated drug resistance. Overall design: Examination of AR, GR, and FOXA1 chromatin binding by ChIP-seq from VCaP and 22Rv1 prostate cancer cells grown in the presence or absence of ENZ. Examination of H3K27ac chromatin occurrence by ChIP-seq from 22Rv1 prostate cancer cells grown in the presence or absence of ENZ. Examination of GR and TLE3 chromatin binding before and after FOXA1 depletion by ChIP-seq from VCaP prostate cancer cells grown in the presence or absence of ENZ. Examination of GR chromatin binding before and after AR-V7 depletion by ChIP-seq from 22Rv1 prostate cancer cells grown in the presence or absence of ENZ. All sequencing was done with Illumina NextSeq 500 or Illumine NextSeq 2000.