Effect of FOXA1 over-expression upon AR binding in AR-driven cancers
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina Genome Analyzer IIx
ORGANISM(S): Homo sapiens
SUBMITTER: Gordon Brown
PROVIDER: E-MTAB-1749 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We performed a comparision of AR binding sites as well as the histone modifications H3K27 acetylation and H3K4 monomethylation in the presence and absence of FoxA1 in the molecular apocrine breast cancer cell line, MDA-MB-453. We also probed AP2alpha binding in asynchronous MDA-MB-453 cells.
2014-04-17 | E-MTAB-1694 | biostudies-arrayexpress
Project description:Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER_ AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER_ AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers.
2012-02-18 | E-MTAB-986 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is the major therapeutic target in prostate cancer, although the important targets of the AR have remained obscure. Here we report a detailed genomic profile of AR signalling and find that the AR directly regulates glycolysis, anabolic metabolism and cell cycle regulators in prostate cancer. This coordinated transcriptional program promotes cancer cell proliferation and enhances the macromolecular synthesis needed to produce daughter cells. Clinical gene expression profiles and mechanistic studies highlight the importance of CAMKK2, an AR target which regulates both cell proliferation and metabolism. Thus our genomics study identifies a direct link between AR signalling and aerobic glycolysis (the Warburg effect), providing a new perspective on the oncogenic function of the AR in prostate cancer. 8 Samples: Chromatin IP using AR and PolII in stimulated and unstimulated LNCaP and VCaP cells.
2011-03-23 | E-GEOD-28126 | biostudies-arrayexpress
Project description:The majority of breast cancer subtypes express androgen receptor (AR) in addition to estrogen receptor α (ERα). Depending on the breast cancer subtype androgen signaling has either stimulatory or inhibitory roles in breast cancer cell growth. We have mapped AR cistrome in ERα negative human molecular apocrine breast cancer MDA-MB453 cells and analyzed it in relation to the androgen-regulated transcriptome in the same cells. We have also examined the effect of silencing of the coregulator SUMO ligase PIAS1 on the androgen-regulated transcriptome and AR cistrome in MDA-MB453 cells. Our results show that the MDA-MB453 cells share with VCaP prostate cancer cells a core AR cistrome and target gene signature linked to cancer cell growth and that PIAS1 acts as an AR target gene-selective coregulator in MDA-MB453 cells. MDA-MB453 cells were transfected with control siRNA (siNON) or PIAS1 siRNA (siPIAS1) for 72 h and treated 16 h with 10 nM R1881 or vehicle (ethanol). Total RNA was isolated and biological triplicate samples were analyzed by microarray.
2016-07-18 | E-GEOD-70162 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.
2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare AR binding activity in LNCaP cells with and without knockdown of GATA2. Methods: LNCaP cells between passage number 32-34 were used for assay. Cells are transfected with GATA2 specific or nonspecific siRNA and ChIP was performed, the ChIP producted was further used to generate library with illumina ChIP-seq kit. Hi-seq 2500 was used for sequencing and the data was analyzed by MACs for peaks. Results: GATA2 knockdown lead to changes of AR binding activity , in most AR binding sites, AR shows decreased bindig activity. Only small percent sites show increased binding. Conclusions: Our study represents the first detailed analysis of the relationship between GATA2 and AR binding in whole genomic DNA.These results demostrate GATA2 play a critical role in AR activity in prostate cancer. LNCaP cells was used as cell model were treated with specific GATA2 siRNA.Library was sequenced using Illumina HI-seq 2500.
2014-01-21 | E-GEOD-52725 | biostudies-arrayexpress
Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Androgen receptor (AR) genomic binding was studied in wild-type AR (wtAR) or SUMOylation-deficient AR (AR-K2R) stably expressing cells PC-3 cells, in biological dublicates. Cells were treated 1h either with 10 nM R1881 or vehicle and inputs were used as controls.
2014-07-03 | E-GEOD-54110 | biostudies-arrayexpress
Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Androgen receptor (AR) genomic binding was studied in wild-type AR (wtAR) or SUMOylation-deficient AR (AR-K2R) stably expressing cells HEK293 cells, in biological dublicates. Cells were treated 40 min either with 10 nM R1881 or EtOH (vehicle) and input was used as control (FRT_input GSM1176703).
2014-07-03 | E-GEOD-54109 | biostudies-arrayexpress
Project description:The effect of transient transfection of a construct designed to over-express the androgen receptor (AR) variant AR-V7 on gene expression in MDA-MB-453 cells was assessed using Affymetrix Gene 2.0 ST arrays. Transfection of an AR-expressing construct or an empty construct served as controls. AR-V7, AR or empty vector was transfected into MDA-MB-453 cells. Cells were treated with vehicle control or DHT.
2015-02-10 | E-GEOD-65738 | biostudies-arrayexpress
Project description:Expansion of a polyglutamine (polyQ) tract in the gene for the androgen receptor (AR) results in partial loss of transactivation function and causes spinobulbar muscular atrophy (SBMA). Modification of AR by small ubiquitin-like modifier (SUMO) reduces AR function in a promoter context-dependent manner. We used microarrays to confirm and demonstrate loss of AR function from polyQ expansion and to test the degree to which AR function is altered by preventing polyQ AR SUMOylation. PC12 cells expressing AR10Q, AR112Q, or nonSUMOylatable AR112Q (KRKR) in the presence or absence of synthetic androgen R1881 were assessed for alterations in AR function by comparing gene expression changes with each AR variant in response to ligand.
2014-08-23 | E-GEOD-50383 | biostudies-arrayexpress