BioProject

Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. More...

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. Less...