|
Status |
Public on Nov 07, 2023 |
Title |
Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ATAC-Seq) |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
Summary |
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 chromatin accessibility by ATAC-seq from VCaP and 22Rv1 prostate cancer cells grown in the presence or absence of ENZ. All sequencing was done with Illumina NextSeq 500.
|
|
|
Contributor(s) |
Paakinaho V, Helminen L |
Citation(s) |
38015476 |
|
Submission date |
Oct 04, 2022 |
Last update date |
Nov 30, 2023 |
Contact name |
Ville Paakinaho |
E-mail(s) |
villepaakinaho@gmail.com
|
Organization name |
University of Eastern Finland
|
Department |
School of Medicine
|
Lab |
Biomedicine
|
Street address |
Yliopistonranta 8
|
City |
Kuopio |
ZIP/Postal code |
70210 |
Country |
Finland |
|
|
Platforms (1) |
GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
Samples (28)
|
|
This SubSeries is part of SuperSeries: |
GSE214757 |
Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer |
|
Relations |
BioProject |
PRJNA887027 |