Stat5-regulated gene expression in human prostate cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17483 | GEO | 2010/04/30
SECONDARY ACCESSION(S): PRJNA118753
REPOSITORIES: GEO
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Project description:Transcription factor Stat5 is constitutively active in human prostate cancer but not in normal prostate epithelium. Stat5 activation is associated with prostate cancer lesions of high histological grades, and is present in the majority of castration-resistant recurrent human prostate cancers. The molecular mechnisms underlying constitutive activation of Stat5 in primary and recurrent human prostate cancer are currently unclear. We used microarrays to detail gene expression regulated by Stat5 in human prostate cancer cells. DU145 human prostate cancer cells were transfected with Stat5a/b siRNA or scramble siRNA as control. After 48 h, the cells were harvested and total RNA was prepared for Affymetrix microarrays.
2010-05-27 | E-GEOD-17483 | biostudies-arrayexpress
Project description:In several cancer types, STAT (Signal transducer and activator of transcription) transcription factors are constitutively activated. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. Here, we demonstrate in transformed hematopoietic cells that binding of both STAT5B and p53 to chromatin is required for transcriptional activity of an alternative LPP/miR-28 promoter. Using a genome-wide approach, we identified 463 genomic positions at promoter regions where STAT5B and p53 are co-localized on the chromatin. At these positions, p53 chromatin binding is dependent on persistent STAT5B activation. The transcriptional activity of selected promoters bound by STAT5B and p53 was significantly changed upon STAT5 or p53 inhibition, and the transcription of these target genes is frequently altered in platelets of myeloproliferative neoplasm patients harboring mutations constitutively activating STAT5. These data suggest that the constitutive STAT5 activation recruits p53 in cancer cells and thereby activates oncogenic transcriptional programs. STAT5B and p53 ChIP-chip with or without JAK2 inhibition (ruxolitinib) to inhibit STAT5 phosphorylation and DNA binding.
2014-02-01 | E-GEOD-38143 | biostudies-arrayexpress
Project description:To identify molecular singnal alterations between androgen dependent prostate cancer and castration resistant prostate cancer, we performed interspecies comparative microarray analyses using RNAs prepared from uncastrasion and castration tumor from LNCAP Orhotopic xenograft models of prostate cancer. microarray data from uncastrasion and castration tumor revealed that the gene expression profile is most significantly altered in between androgen dependent prostate cancer and castration resistant prostate cancer. Comparative analyses of LNCAP Orhotopic xenograft models of prostate cancer showed that genes involved in androgen dependent and androgen independent tumor were significantly altered. We prepared RNA samples from 4 samples uncastrasion and 4 samples castration tumors from LNCAP Orhotopic xenograft models of prostate cancer . High-quality RNA samples were subjected to microarray analysis using the Affymetrix Human Gene 2.0 ST platform, and only those results that passed examinations for quality assurance and quality control of the Human Gene 2.0 ST arrays were retrieved. In total, we obtained gene expression profiles from the following samples: 4 samples uncastrasion and 4 samples castration tumors
2013-04-20 | E-GEOD-46218 | biostudies-arrayexpress
Project description:Recurrent gain-of-function mutations in the transcription factor STAT5 have been detected in PTCL, an aggressive, heterogeneous disease, for which currently no targeted therapy exists. Here we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. We found pronounced STAT5 expression and activity in patients from different PTCL subsets. To mimic high STAT5 activity we expressed a hyperactive STAT5A variant (termed vcS5) in the hematopoietic lineage in transgenic mice. vcS5-transgenic animals developed a lethal PTCL-like disease with full penetrance, characterized by massive expansion of CD8+ T-cells and destructive organ-infiltration. Adoptive transfer of vcS5-expressing CD8+ T-cell rapidly induced the disease in immunocompetent recipient mice. Neoplastic vcS5-T-cells displayed cytokine-hypersensitivity and showed activated, memory CD8+ T-lymphocyte characteristics. Histo-pathological analysis as well as mRNA expression profiles of vcS5 mice was closely correlated with distinct human lymphoma subtypes, including PTCL. Treatment of murine and human PTCL cell lines with the clinical JAK inhibitor Ruxolitinib or a selective STAT5 SH2 domain inhibitor induced cell death. Thus, our results demonstrate that enhanced STAT5 signaling drives PTCL development and suggest inhibition of the JAK/STAT5 pathway as a valuable therapeutic option for patients suffering from these aggressive lymphomas.
2017-10-18 | GSE74176 | GEO
Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer stem cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOC3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
2019-11-11 | PXD013245 | Pride
Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells
2013-12-09 | E-GEOD-51283 | biostudies-arrayexpress
Project description:More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. 4 samples in each group: androgen-dependent growth (AD), castration-induced regression nadir (ND), and castration-resistant regrowth (CR) stages
2010-06-08 | E-GEOD-21887 | biostudies-arrayexpress
Project description:In several cancer types, STAT (Signal transducer and activator of transcription) transcription factors are constitutively activated. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. Here, we demonstrate in transformed hematopoietic cells that binding of both STAT5B and p53 to chromatin is required for transcriptional activity of an alternative LPP/miR-28 promoter. Using a genome-wide approach, we identified 463 genomic positions at promoter regions where STAT5B and p53 are co-localized on the chromatin. At these positions, p53 chromatin binding is dependent on persistent STAT5B activation. The transcriptional activity of selected promoters bound by STAT5B and p53 was significantly changed upon STAT5 or p53 inhibition, and the transcription of these target genes is frequently altered in platelets of myeloproliferative neoplasm patients harboring mutations constitutively activating STAT5. These data suggest that the constitutive STAT5 activation recruits p53 in cancer cells and thereby activates oncogenic transcriptional programs.
2014-02-01 | GSE38143 | GEO
Project description:We report the gene expression profile of 8 metastatic castration resisistant prostate cancer samples analyzed by paired-end RNA-seq. We found evidence of extensive abnormal splicing as well as several novel fusion genes. Finally, we also observed several recurrent high-confidence somatic mutations. Paired-end RNA-seq by rRNA depletion
2014-09-06 | E-GEOD-50630 | biostudies-arrayexpress
Project description:Androgens are a prequisite for the development of human prostate and prostate cancer. Androgen action is mediated via androgen receptor. Androgen ablation therapy is used for the treatment of metastasized prostate cancer. The aim of the study was to identify genes differentially expressed in benign human prostate, prostate cancer and in prostate tissue three days after castration. These genes are potential diagnostic and therapeutic targets for prostate cancer and benign prostatic hyperplasia. We used microarrays to examine the gene expression profiles in benign prostate adjacent to prostate cancer and prostate cancer in radical prostatectomy specimens and in prostate tissue samples taken 3 days after surgical castration performed for treatment of prostate cancer. Human prostate tissue was obtained from radical prostatectomy samples and from prostate biopsy samples (castrated samples). Benign and malignant tissues samples were microdissected from prostatectomy samples. Tissues were used for RNA isolation and were further processed as samples for microarray. Three prostatectomy samples were used as replicates (benign and malignant prostate). All prostate cancers were Gleason 3+3 pattern. Castrated tissue samples were taken from patients three days after surgical castration for the treatment of advanced or metastasized prostate cancer. Six biopsies were taken from each subject and individual subject samples were used as three replicates in microarray.
2012-06-19 | E-GEOD-32982 | biostudies-arrayexpress