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Identification of the GATA2 transcriptome in the AR-V positive castrate-resistant prostate cancer cell line CWR22Rv1

ABSTRACT: To interrogate the extent of overlap between GATA2 and AR-V regulated transcriptomes in castrate-resistant prostate cancer cells, we assessed global gene expression changes in GATA2-depleted CWR22Rv1 cells by microarray analysis using the Illumina Human HT-12 BeadChip array and compared GATA2 regulated genes to a previously generated AR-V regulated genset (Jones et al., 2015). We identified that AR-V transcriptional activity is dependant upon GATA2 at a subset of its target genes. GATA2 also regulated the expression of c-Myc and E2F1 regulated transcriptional targets amongst other oncogenic transcription factors. Transcripts regulated by GATA2 were highly enriched in the cell cycle.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124999 | GEO | 2019/01/12

REPOSITORIES: GEO

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Identification of the GATA2 transcriptome in the AR-V positive castrate-resistant prostate cancer cell line CWR22Rv1

Project description:Identification of the GATA2 transcriptome in the AR-V positive castrate-resistant prostate cancer cell line CWR22Rv1

| PRJNA514807 | ENA

Determining the impact of the Bromodomain and extra-terminal inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer

Project description:To determine the impact of the Bromodomain and extra-terminal (BET) inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer we performed GATA2 ChIP-seq in the presence and absence of JQ1 and assessed differential binding upon JQ1 treatment for 24 hours. We first determined the GATA2 cistrome using our GATA2 ChIP-seq data. Overlapping this with previously published ChIP-seq data for the BET family of proteins (Asangani et al., 2014), we identified a substantial proportion of GATA2 genomic binding sites which are co-occupied by a BET protein. We then quantified differential binding of GATA2 upon JQ1 treatment genome-wide.

2019-01-17 | GSE125236 | GEO

Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [ChIP-Seq]

Project description:AR is tightly regulated by many transcriptional cofactors, including key pioneer factor such as FOXA1 and GATA2. While FOXA1 was recently shown to be able to redistribute AR across the genome, how GATA2 regulates AR cistrome has not been carefully investigated. Here, we report that, unlike FOXA1, GATA2 is unable to reprogram AR, but instead it enhances AR program by inducing AR expression and augmenting AR co-occupancy, thereby acting as a pure AR coactivator, rather than a pioneer factor. On the other hand, AR co-occupancy enhances both GATA2 and FOXA1 binding on the chromatin, forming a positive feedback loop. Importantly, we found that FOXA1 is also capable of reprogramming GATA2 by recruiting GATA2 from GATA motif to FKHD-containing regions, being analogous to its pioneering effect on AR signaling. By contrast, GATA2 simply acts as a co-activator of FOXA1 with a lack of pioneering ability. ChIP_Seq examination of AR, FoxA1 and GATA2 binding sites in LNCaP and DU145 cells

2016-01-11 | E-GEOD-69043 | biostudies-arrayexpress

Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [gene expression]

2016-01-11 | E-GEOD-69044 | biostudies-arrayexpress

Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [ChIP-Seq]

2016-01-11 | GSE69043 | GEO

Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [gene expression]

2016-01-11 | GSE69044 | GEO

GATA2 facilitates steroid receptor coactivator (SRC) recruitment to the androgen receptor (AR) complex

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

GATA2 facilitates steroid receptor coactivator (SRC) recruitment to the androgen receptor (AR) complex

2015-01-21 | GSE63539 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of effect of knockdown of GATA2 on AR binding sites

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

The role of the transcription factors GATA2 and FOXA1 in immortalized basal-like prostate epithelial cells

Project description:GATA2 and FOXA1 are pioneering factors for Androgen Receptor (AR) in prostate cancer cells. Less is known about their role in benign epithelial prostate cells. We investigated if they had the ability to induce differentiation in an undifferentiated prostatic context. Benign basal-like prostate epithelial cells 957E/hTERT-AR cells (a gift from John T. Isaacs lab, Johns Hopkins, MD, USA) were transduced with LentiORF RFP control lentiviral particles. The 957E/hTERT-AR-RFP cells were then transduced with GATA2 and FOXA1 lentiviral particles, and we called the new cell lines hTERT/AR-GATA2 and hTERT/AR-FOXA1, respectively. hTERT/AR-GATA2 is a stable selected cell line and treated with 1 nM anabolic steroids, R1881, or ethanol (ET-OH) for 48 hrs. 957E/hTERT/AR-FOXA1 is a transient cell line, because FOXA1 protein is quickly lost. Twenty four hours post transduction with FOXA1 lentivral particles, 1 nM androgen R1881 or ethanol (ET-OH) were added at time for medium exchange and further treated for 24 hours. GATA-2 and FOXA1 ability to induce differentiation was assessed.

2018-12-01 | E-MTAB-5121 | biostudies-arrayexpress

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