Differential modulation of the androgen receptor for prostate cancer therapy depends on the DNA response element
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ABSTRACT:
PROVIDER: PRJNA564340 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10082138_1.fastq.gz | Fastqsanger.gz | |||
| SRR10082138_2.fastq.gz | Fastqsanger.gz | |||
| SRR10082139_1.fastq.gz | Fastqsanger.gz | |||
| SRR10082139_2.fastq.gz | Fastqsanger.gz | |||
| SRR10082140_1.fastq.gz | Fastqsanger.gz |
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Project description:Androgen receptor (AR) action is a hallmark of prostate cancer (PCa) with androgen deprivation being standard therapy. Yet, resistance arises and aberrant AR signaling promotes disease. We sought compounds that inhibited genes driving cancer but not normal growth and hypothesized that genes with consensus androgen response elements (cAREs) drive proliferation but genes with selective elements (sAREs) promote differentiation. In a high-throughput promoter-dependent drug screen, doxorubicin (dox) exhibited this ability, acting on DNA rather than AR. This dox effect was observed at low doses for multiple AR target genes in multiple PCa cell lines and also occurred in vivo. Transcriptomic analyses revealed that low dox downregulated cell cycle genes while high dox upregulated DNA damage response genes. In chromatin immunoprecipitation (ChIP) assays with low dox, AR binding to sARE-containing enhancers increased, whereas AR was lost from cAREs. Further, ChIP-seq analysis revealed a subset of genes for which AR binding in low dox increased at pre-existing sites that included sites for prostate-specific factors such as FOXA1. AR dependence on cofactors at sAREs may be the basis for differential modulation by dox that preserves expression of genes for survival but not cancer progression. Repurposing of dox may provide unique opportunities for PCa treatment.
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Project description:Prostate epithelial cells depend on androgens for survival and function. In early prostate cancer, besides survival, androgens also regulated tumor growth, which is exploited by androgen ablation/ blockade therapies in metastatic disease. The aim of the present study was to characterize the role of the androgen receptor pathway in prostate cancer progression and to identify potential disease markers. Microarray analysis was used to establish the androgen-regulated gene expression profile, upon stimulation with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide, of the androgen-responsive PC346C cell line and its derivative castration-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A mutated AR) PC346C, PC346DCC, PC346Flu1 and PC346Flu2 were stimulated with 1 nM R1881, 1uM hydroxyflutamide or vehicle control, following a 4, 8 and 16h time-course. Each condition was performed in dye-swap, using biological duplicates. PC346DCC was only stimulated with R1881, not hydroxyflutamide.
2011-08-04 | E-GEOD-22914 | biostudies-arrayexpress
Project description:Prostate epithelial cells depend on androgens for survival and function. In early prostate cancer, besides survival, androgens also regulated tumor growth, which is exploited by androgen ablation/ blockade therapies in metastatic disease. The aim of the present study was to characterize the role of the androgen receptor pathway in prostate cancer progression and to identify potential disease markers. Microarray analysis was used to establish the androgen-regulated gene expression profile, upon stimulation with the synthetic androgen R1881 or the antiandrogen hydroxyflutamide, of the androgen-responsive PC346C cell line and its derivative castration-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A mutated AR)
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Project description:We report the in vivo androgen receptor (AR) binding sites in caput epididymis of intact SPARKI and wild-type mice using ChIP-sequencing. SPARKI (specificity affecting androgen receptor knock-in) mouse line has the second zinc finger of AR replaced by that of glucocorticoid receptors. In vivo analysis of SPARKI and wild-type AR genome-wide binding sites identified cis-element with less stringent sequence requirements that specify selective AR-binding sites. The ChIP experiments have been performed using antibody specific to AR and IgG non-specific antibody as a negative control.
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Project description:We report the in vivo androgen receptor (AR) binding sites in caput epididymis of intact SPARKI and wild-type mice using ChIP-sequencing. SPARKI (specificity affecting androgen receptor knock-in) mouse line has the second zinc finger of AR replaced by that of glucocorticoid receptors. In vivo analysis of SPARKI and wild-type AR genome-wide binding sites identified cis-element with less stringent sequence requirements that specify selective AR-binding sites. The ChIP experiments have been performed using antibody specific to AR and IgG non-specific antibody as a negative control. Examination of AR binding sites in epididymis of wild-type and SPARKI mice using ChIP-seq. Two biological replicates from intact wild-type and SPARKI mice and two control IgG samples were sequenced and used in peak calling. To increase the depth of the analysis, replicate ChIP-seq samples were merged and the concatanated samples were used in peak calling.
2014-01-21 | E-GEOD-51106 | biostudies-arrayexpress
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2011-04-07 | E-GEOD-27410 | biostudies-arrayexpress
Project description:Androgen-stimulated growth of the molecular apocrine breast cancer is mediated by an androgen receptor (AR)-regulated transcriptional program. Through profiling the genomic licalizations of AR and its co-regulators FOXA1 and TCF7L2 in MDA-MB-453 breast cancer cells, we revealed the molecular details of the AR-centered regulatory network. We further identified that c-MYC is a key downstream target co-regulated by AR, FOXA1 and TCF7L2, and reinforces the transctiopnal activation of androgen-responsive genes in this subtype of breast cancers. MDA-MB-453 breast cancer cells were transfected with control of MYC siRNA for 48 h, followed by treatment with 10nM DHT or vehicle for 6 h. The cells were subjected to mRNA purification and library praparation for RNA-seq on Illumina HiSeq2000 platform.
2013-03-16 | E-GEOD-45202 | biostudies-arrayexpress
Project description:Androgen-stimulated growth of the molecular apocrine breast cancer is mediated by an androgen receptor (AR)-regulated transcriptional program. Through profiling the genomic licalizations of AR and its co-regulators FOXA1 and TCF7L2 in MDA-MB-453 breast cancer cells, we revealed the molecular details of the AR-centered regulatory network. We further identified that c-MYC is a key downstream target co-regulated by AR, FOXA1 and TCF7L2, and reinforces the transctiopnal activation of androgen-responsive genes in this subtype of breast cancers. AR and FOXA1 ChIP-seq were performed in MDA-MB-453 breast cancer cells with treatment of 5a-dihydrotestosterone (DHT) for 16 h. TCF7L2 ChIP-seq was performed in MDA-MB-453 cells treated with vehicle or DHT for 16 h, respectively. MYC ChIP-seq was performed in MDA-MB-453 cells following 6 h DHT stimulation.
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