Similar Datasets
Project description: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.
2023-11-07 | GSE214756 | GEO
Project description: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.
2023-11-07 | GSE214754 | GEO
Project description: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.
2023-11-07 | GSE214753 | GEO
Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer
| PRJNA887022 | ENA
Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (RNA-Seq)
| PRJNA887025 | ENA
Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ATAC-Seq)
| PRJNA887027 | ENA
Project description:Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer (ChIP-Seq)
| PRJNA887026 | ENA
Project description:Ligand-dependent transcription by the nuclear receptor glucocorticoid receptor (GR) is mediated by interactions with coregulators. The role of these interactions in determining selective binding of GR to regulatory elements remains unclear. Recent findings indicate that a large fraction of genomic GR binding coincides with chromatin that is accessible prior to hormone treatment, suggesting that receptor binding is dictated by proteins that maintain chromatin in an open state. Combining DNaseI accessibility and chromatin immunoprecipitation with high-throughput sequencing, we identify the activator protein 1 (AP1) as a major partner for productive GR-chromatin interactions. AP1 is critical for GR-regulated transcription and recruitment to co-occupied regulatory elements, illustrating an extensive AP1-GR interaction network. Importantly, the maintenance of baseline chromatin accessibility facilitates GR recruitment and is dependent on AP1 binding. We propose a model in which the basal occupancy of transcription factors acts to prime chromatin and direct inducible transcription factors to select regions in the genome.
| S-EPMC3138120 | biostudies-literature
Project description:Development, differentiation and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from a myriad of potential genomic binding sites is undetermined. Here we show that up to 95% of de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to preexisting foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocorticoid receptor occupancy patterns appear to be comprehensively predetermined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a framework for understanding regulatory factor-genome interactions and provide a molecular basis for the tissue selectivity of steroid pharmaceuticals and other agents that intersect the living genome.
| S-EPMC6386452 | biostudies-literature
Project description:Although a majority of breast cancers (BrCa) are Estrogen receptor-alpha (ERa)-positive, existing endocrine therapies that target ERa can lead to hormone-resistant disease. The mechanisms of how normal breast epithelium is transformed into malignant remain poorly defined, and a deeper understanding is needed to design novel therapeutics. Several epigenetic regulators including long non-coding RNAs (lncRNAs) are aberrantly expressed in BrCa, resulting in abnormal gene expression patterns and tumor growth. Here, we show that HOTAIRM1, which we previously defined as a p53-regulated lncRNA in human stem cells, acts as a tumor suppressor to counteract ERa-activity in BrCa. Global expression analyses uncovered a significant correlation between reduced HOTAIRM1 expression and poor survival of ER+ BrCa patients. Promoter DNA methylation and histone mark enrichment revealed that HOTAIRM1 is epigenetically silenced in BrCa patients and cell lines. We found that HOTAIRM1 depletion promotes, whereas exogenous HOTAIRM1 reduces survival and proliferation of BrCa cells. Guilt by association analysis in BrCa patients, combined with HOTAIRM1-dependent transcriptome profiling in BrCa cells reveal that HOTAIRM1 expression negatively correlates with proteins involved in ERa-activity and estrogen response. An unbiased profiling of HOTAIRM1-interactome show that HOTAIRM1 interacts with pioneer factor FOXA1 in ER+ BrCa cells. Further, our global ER/FOXA1 chromatin enrichment profiling in response to estrogen demonstrate increased enrichment of ER and FOXA1 to estrogen response elements (EREs) that results in significantly higher expression of ERa-targets in absence of HOTAIRM1. Thus, HOTAIRM1 suppresses ERa-activity in BrCa by restricting chromatin accessibility of pioneer factor FOXA1. To our knowledge, our results are the first to define a non-proteomic component that disrupts the activity of a pioneer factor in order to achieve tumor suppression
2023-08-15 | GSE135894 | GEO