Targeting GATA2 in prostate cancer with dilazep (1)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147175 | GEO | 2025/03/15
REPOSITORIES: GEO
Similar Datasets
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: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 | GSE147214 | GEO
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: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: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:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.
2012-03-17 | E-GEOD-36549 | biostudies-arrayexpress
Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies.
2012-03-17 | GSE36549 | GEO
Project description:The androgen receptor (AR) is the major transcriptional driver of prostate cell growth in man. For the first time, we define AR targets in prostate cancer (PC) tissue representing progression from treatment-naive to castrate-resistant disease (CRPC). We employed chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies. We uncovered an AR transcriptional network not observed in cultured cells, with significant over-representation of MYC, E2F and STAT binding sites, progenitor cell gene signatures and targets which regulate metabolism, cell cycle and steroid biosynthesis. We identified AR targets unique to CRPC tissue, with a subset over-expressed in CRPC and predictive of clinical outcome, highlighting persistence of AR signalling. Our data support a model whereby endocrine and paracrine signals converge on the AR in PC tissue to drive oncogenic transcriptional programs, highlighting the critical role of cellular context in the regulation of target selection and gene expression. chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies
2013-01-04 | E-GEOD-28219 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is the major transcriptional driver of prostate cell growth in man. For the first time, we define AR targets in prostate cancer (PC) tissue representing progression from treatment-naive to castrate-resistant disease (CRPC). We employed chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies. We uncovered an AR transcriptional network not observed in cultured cells, with significant over-representation of MYC, E2F and STAT binding sites, progenitor cell gene signatures and targets which regulate metabolism, cell cycle and steroid biosynthesis. We identified AR targets unique to CRPC tissue, with a subset over-expressed in CRPC and predictive of clinical outcome, highlighting persistence of AR signalling. Our data support a model whereby endocrine and paracrine signals converge on the AR in PC tissue to drive oncogenic transcriptional programs, highlighting the critical role of cellular context in the regulation of target selection and gene expression.
2013-01-04 | GSE28219 | GEO
Project description:Advanced prostate cancer (PC) can be treated with endocrine therapies that inhibit transcriptional activity of the androgen receptor (AR). However, PC will ultimately evolve under the selection pressure of these therapies and progress to a lethal phenotype termed castration-resistant PC (CRPC). Recent studies suggest that de-differentiation away from an AR-driven luminal cell identity may be a key, early step. However, early therapy-induced mechanisms of prostate cancer cell de-differentiation are poorly understood. Here we show that the stem cell transcription factor Kruppel-like factor 5 (KLF5) is transcriptionally repressed by AR, and de-repressed by enzalutamide. KLF5 expression is high in a subset of CRPC tissues, but low in primary adenocarcinoma. KLF5 functioned as oncogene in CPRC cells, promoting cellular migration, anchorage-independent growth, expression of basal cell markers, and transcriptional signatures of CRPC lineage plasticity, but had modest effects on cell proliferation. Chromatin immuno-precipitation (ChIP)-sequencing, RNA-sequencing, and co-immunoprecipitation experiments established a physical interaction between KLF5 and AR, and integrative analysis revealed that KLF5 and AR drive opposing transcriptional programs. We identified ERBB2 as a point of transcriptional convergence that was activated by KLF5 and repressed by AR. Accordingly, KLF5 expression levels in CRPC tissues correlated with predicted sensitivity to the dual EGFR inhibitor lapatanib, and the ERBB2-specific inhibitor mubritinib blocked KLF5-driven cell migration. Collectively, these findings implicate KLF5 as an AR-suppressed oncogene that drives early steps in CRPC de-differentiation and disease progression.
2021-09-21 | GSE148807 | GEO