The ETS family member GABPa mediates the development of castrate-resistant prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49093 | GEO | 2014/05/21
SECONDARY ACCESSION(S): PRJNA213012
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-21 | E-GEOD-49093 | biostudies-arrayexpress
Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes.
2014-05-21 | GSE49083 | GEO
Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. Cells were made to either overexpress GABPa or have it knocked down; these conditions also had empty vector and non-targetting controls respectively. All four treatments were carried out with and without androgen for the LNCaP and c42b cell lines. Biological and technical replicates were used.
2014-05-21 | E-GEOD-49083 | biostudies-arrayexpress
Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes.
2014-05-21 | GSE49091 | GEO
Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. VCaP prostate cancer cells and Jurkat lymphoma cells were studied for the ETS factors ERG and GABPa binding sites. Each sample was compared to its input.
2014-05-21 | E-GEOD-49091 | biostudies-arrayexpress
Project description:In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.
| S-EPMC4041454 | biostudies-literature
Project description:Purpose of reviewPrior to 2010, docetaxel was the only treatment shown to prolong survival in metastatic castrate-resistant prostate cancer (CRPC). In the past 3 years, several therapeutic agents have demonstrated survival improvements for CRPC after the receipt of prior docetaxel, leading to multiple approvals by the US Food and Drug Administration.Recent findingsThe development of these novel agents, each with a distinct mechanism of action, is the fruition of sedulous preclinical research and well designed clinical trials. Cabazitaxel, a next generation taxane, was the first Food and Drug Administration-approved drug for the postdocetaxel setting. The recognition of sustained androgen dependence of CRPC has led to the identification of more potent and selective inhibitors of androgen synthesis and androgen-receptor signaling, such as abiraterone and enzalutamide, respectively. Radium-223, an α-emitting radionuclide still under regulatory review, recently showed a significant survival benefit for CRPC. Finally, sipuleucel-T, a form of immunotherapy, may benefit a subset of patients in the postdocetaxel setting.SummaryPost-docetaxel management of CRPC has undergone a dramatic yet welcome paradigm change in the past 3 years. With multiple life-prolonging agents available, it now becomes imperative to coordinate how and when these new therapies should be used and sequenced to achieve optimal patient outcomes.
| S-EPMC4486479 | biostudies-literature
Project description:There is a tremendous need for novel strategies aimed at directly assessing activities of histone modifiers to probe epigenetic determinants associated with disease progression. Here, we developed a high-throughput peptide microarray assay to identify altered histone lysine (de)acetylation activity in prostate cancer (PCa). This microarray-based activity assay revealed up-regulated histone acetyltransferase (HAT) activity against specific histone H3 sites in a castrate-resistant (CR) PCa cell line compared to its hormone-sensitive (HS) isogenic counterpart. NAD+-dependent deacetylation assays revealed down-regulated sirtuin activity in validated CR lines. Levels of acetyltransferases GCN5, PCAF, CBP, and p300 were unchanged between matched HS and CR cell lines. However, autoacetylation of p300 at K1499, a modification known to enhance HAT activity and a target of deacetylation by SIRT2, was highly elevated in CR cells, while SIRT2 protein level was reduced in CR cells. Interrogation of HS and matched CR xenograft lines reveals that H3K18 hyperacetylation, increased p300 activity, and decreased SIRT2 expression are associated with progression to CR in 8/12 (66%). Tissue microarray analysis revealed that hyperacetylation of H3K18 is a feature of CRPC. Inhibition of p300 results in lower H3K18ac levels and increased expression of androgen receptors. Thus, a novel histone array identifies altered enzyme activities during the progression to CRPC and may be utilized in a personalized medicine approach. Reduced SIRT2 expression and increased p300 activity lead to a concerted mechanism of hyperacetylation at specific histone lysine sites (H3K9, H3K14, and H3K18) in CRPC.
| S-EPMC6594041 | biostudies-literature
Project description:The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.
| S-EPMC3678432 | biostudies-literature
Project description:Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.
| S-EPMC4176261 | biostudies-literature