Targeting GATA2 in prostate cancer with K11706 (2)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147214 | GEO | 2025/03/15
REPOSITORIES: GEO
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Project description:We investigated the role of GATA2 in prostate cancer cells beyond the AR signaling axis, and characterized the pharmacological potency of the GATA2 small molecule inhibitor (SMI) K-11706 against prostate cancer cells. K-11706, which inhibited the proliferation and invasive behavior of PC cells, and dramatically reduced the genome-wide transcriptional activity of GATA2, AR, and cMyc, leading to downregulation of several prostate cancer drivers and AR/cMyc effector genes, notably FOXM1, EZH2, and CENPF. Transcriptional profiling and functional pathway analysis of the K-11706 transcriptomic footprint against curated databases delineated a biological network composed of genes involved in cell cycle/proliferation, stemness, metastasis and DNA repair.
2025-03-15 | GSE147173 | GEO
Project description:Using a bioinformatics algorithm, we screened in silico 2,650 clinically relevant drugs for a potential GATA2 inhibitor. We identified the vasodilator Dilazep as a potential GATA2 inhibitor. Dilazep exerted anticancer activity across a broad panel of PC cell lines. Global gene expression analysis revealed that dilazep suppressed the GATA2, AR, and cMyc transcriptional programs, including under CRPC conditions. We also documented suppression of cell cycle programs and decreased expression of oncogenic drivers, such as FOXM1, CENPF, EZH2, UBE2C, RRM2, as well as several mediators of metastasis, DNA damage repair and stemness. We provide, based on global gene expression analysis, proof-of-principle evidence that a small molecule can inhibit GATA2 in PC cells and can suppress its downstream AR, cMyc, and other cancer-driving effectors. We propose that GATA2 can be a therapeutic target in CRPC.
2025-03-15 | GSE147175 | GEO
Project description:Using a bioinformatics algorithm, we screened in silico 2,650 clinically relevant drugs for a potential GATA2 inhibitor. We identified the vasodilator Dilazep as a potential GATA2 inhibitor. Dilazep exerted anticancer activity across a broad panel of PC cell lines. Global gene expression analysis revealed that dilazep suppressed the GATA2, AR, and cMyc transcriptional programs, including under CRPC conditions. We also documented suppression of cell cycle programs and decreased expression of oncogenic drivers, such as FOXM1, CENPF, EZH2, UBE2C, RRM2, as well as several mediators of metastasis, DNA damage repair and stemness. We provide, based on global gene expression analysis, proof-of-principle evidence that a small molecule can inhibit GATA2 in PC cells and can suppress its downstream AR, cMyc, and other cancer-driving effectors. We propose that GATA2 can be a therapeutic target in CRPC.
2025-03-15 | GSE147215 | GEO
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: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
Project description:Metastatic prostate cancer (PCa) is a terminal disease and establishment of novel therapeutic strategy specifically targeting metastasis is critically required for its management. This study was aimed at identifying metastasis-driving genes which could potentially be therapeutic targets for metastatic prostate cancer. Integrative analysis of gene expression profiles from a pair of metastatic and non-metastatic prostate cancer tissue xenografts was used to identify potential prostate cancer metastasis-driving genes. Among the candidate genes found, GATA2, a master regulator gene in the development of hematopoietic system, was particularly interesting since it is an important pioneer factor in the regulation of AR-target gene in prostate cancer. In consistent with our finding, elevated expression of the GATA2 gene in metastatic prostate cancers was found and its expression was significantly correlated with poor prognosis in prostate cancer patients. Furthermore, indication of the GATA2 gene maybe the metastasis-driving gene was evidenced in decreased of cell migration, tissue invasion and focal adhesion disassembly in GATA2-down-regulated LNCaP cells. Global gene expression analysis after silencing of the GATA2 gene revealed a significant changed in cell transcriptomes with ~ 2500 genes with > 2 fold mRNA level changed and FDR <0.05, indicates that GATA2 plays a critical role in cell reprogramming as pioneer factor in the development of prostate cancer metastasis. LNCaP human prostate cancer cells transiently knockdown with siRNA that specifically targeting GATA2 (siGATA2) or scrambled siRNA (sicontrol). RNAs were isolated from cells after 72 hours of incubation. Gene expression profiles of four biological replicates from each sample group were analyzed to identify differentially regulated downstream genes after knockdown of GATA2.
2014-01-20 | E-GEOD-49342 | 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.
2015-01-21 | GSE63539 | GEO
Project description:Metastatic prostate cancer (PCa) is a terminal disease and establishment of novel therapeutic strategy specifically targeting metastasis is critically required for its management. This study was aimed at identifying metastasis-driving genes which could potentially be therapeutic targets for metastatic prostate cancer. Integrative analysis of gene expression profiles from a pair of metastatic and non-metastatic prostate cancer tissue xenografts was used to identify potential prostate cancer metastasis-driving genes. Among the candidate genes found, GATA2, a master regulator gene in the development of hematopoietic system, was particularly interesting since it is an important pioneer factor in the regulation of AR-target gene in prostate cancer. In consistent with our finding, elevated expression of the GATA2 gene in metastatic prostate cancers was found and its expression was significantly correlated with poor prognosis in prostate cancer patients. Furthermore, indication of the GATA2 gene maybe the metastasis-driving gene was evidenced in decreased of cell migration, tissue invasion and focal adhesion disassembly in GATA2-down-regulated LNCaP cells. Global gene expression analysis after silencing of the GATA2 gene revealed a significant changed in cell transcriptomes with ~ 2500 genes with > 2 fold mRNA level changed and FDR <0.05, indicates that GATA2 plays a critical role in cell reprogramming as pioneer factor in the development of prostate cancer metastasis.
2014-01-20 | GSE49342 | GEO
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: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.
2019-01-12 | GSE124999 | GEO