ShRNA-mediated knockdown of ETV4 and MED25 in the prostate cell line PC3 reveals set of genes potentially coregulated by MED25 and ETV4
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ABSTRACT:
PROVIDER: PRJNA551469 | ENA |
REPOSITORIES: ENA
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Project description:Our in vitro binding studies support a model whereby MED25 exhibits multivalent interactions with a subset of related ETS factors, ETV1/4/5. We hypothesize that the interaction would allow for coregulation of genes by ETV1/4/5 and MED25, acting perhaps to link the ETVs to the Mediator complex. To explore this possibility, we compared the genome occupancy for FLAG-tagged MED25 and ETV4 in the prostate cancer cell line PC3, which overexpresses ETV4. We also tested for relevance of MED25 and ETV4 binding to for gene expression in PC3s. We found a high degree of overlap in the FLAG-MED25 and ETV4 ChIPs datasets consistent with our model, and also identified a subset of target genes co-dependent on Med25 and ETV4.
2019-06-28 | GSE133447 | GEO
Project description:Our in vitro binding studies support a model whereby MED25 exhibits multivalent interactions with a subset of related ETS factors, ETV1/4/5. We hypothesize that the interaction would allow for coregulation of genes by ETV1/4/5 and MED25, acting perhaps to link the ETVs to the Mediator complex. To explore this possibility, we compared the genome occupancy for FLAG-tagged MED25 and ETV4 in the prostate cancer cell line PC3, which overexpresses ETV4. We also tested for relevance of MED25 and ETV4 binding to for gene expression in PC3s. We found a high degree of overlap in the FLAG-MED25 and ETV4 ChIPs datasets consistent with our model, and also identified a subset of target genes co-dependent on Med25 and ETV4.
2019-06-28 | GSE133445 | GEO
Project description:Genome-wide occupancy of FLAG-MED25 and ETV4 and expression profiling of shRNA-mediated knockdown of ETV4 and MED25 in the prostate cell line PC3
| PRJNA551467 | ENA
Project description:Genome-wide occupancy of FLAG-MED25 and ETV4 in PC3 cells
| PRJNA551468 | ENA
Project description:Chromosomal abnormalities that give rise to elevated expression levels of the ETS genes ETV1, ETV4, ETV5, or ERG are prevalent in prostate cancer, but the function of these transcription factors in carcinogenesis is not clear. Previous work implicates ERG, ETV1, and ETV5 as regulators of invasive growth but not transformation in cell lines. Here we show that the PC3 prostate cancer cell line provides a model system to study the over-expression of ETV4. Anchorage independent growth assays and microarray analysis indicate that high ETV4 expression is critical for the transformation phenotype of PC3 cells. However, genes up-regulated upon ETV4 over-expression were very similar to genes up-regulated by ETV1 over-expression in the RWPE-1 normal prostate cell line. Together these data indicate that the ETV4 dependent transformation phenotype observed in PC3 cells is due to the genetic background of the cell line, rather than a distinct characteristic of ETV4. Furthermore, these findings suggest that the function of ETS genes in prostate cancer may differ based on other genetic alterations in a tumor. Two sets of two color experiments. First is PC3 cells expressing one of two independent ETV4 shRNAs versus PC3 cells expressing a control shRNA (luciferase). Second is RWPE-1 cells expressing 3xFlag tagged ETV4 versus RWPE-1 cells with a control (empty) vector.
2011-03-24 | E-GEOD-21209 | biostudies-arrayexpress
Project description:Chromosomal abnormalities that give rise to elevated expression levels of the ETS genes ETV1, ETV4, ETV5, or ERG are prevalent in prostate cancer, but the function of these transcription factors in carcinogenesis is not clear. Previous work implicates ERG, ETV1, and ETV5 as regulators of invasive growth but not transformation in cell lines. Here we show that the PC3 prostate cancer cell line provides a model system to study the over-expression of ETV4. Anchorage independent growth assays and microarray analysis indicate that high ETV4 expression is critical for the transformation phenotype of PC3 cells. However, genes up-regulated upon ETV4 over-expression were very similar to genes up-regulated by ETV1 over-expression in the RWPE-1 normal prostate cell line. Together these data indicate that the ETV4 dependent transformation phenotype observed in PC3 cells is due to the genetic background of the cell line, rather than a distinct characteristic of ETV4. Furthermore, these findings suggest that the function of ETS genes in prostate cancer may differ based on other genetic alterations in a tumor.
2011-03-25 | GSE21209 | GEO
Project description:Comparision of transcriptome of PC3 and 22Rv1 prostate cell lines after 1 week overexpression of mutated ETV4: ETV4AAA-IRES-eGFP, wild type ETV4: ETV4WT-IRES-eGFP, and control vector IRES-eGFP by MSCV-IRES-GFP vector ((Addgene #20672)) and Lentivirus transduction.
2022-10-16 | GSE215437 | GEO
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress
Project description:ETS-related transcription factors ETV4 and ETV5 play crucial roles for organogenesis and morphogenesis. We compared the transcriptional profiles between wild-type and ETV4 and ETV5 double knockout (ETV4/5 dKO) ES cells by an oligo DNA microarray analysis. Self-renewal capacity and pluripotency are known to be controlled by an ES cell-specific transcription factor network; therefore, we focused on transcription-associated genes. Of 1258 transcription-related genes, 47 genes were significantly downregulated and 98 genes were significantly upregulated in ETV4/5 dKO ES cells. Several genes whose expression is specific to undifferentiated ES were repressed in ETV4/5 dKO ES cells. In contrast, expression of differentiation markers was enhanced in ETV4/5 dKO ES cells.
2015-09-13 | GSE47225 | GEO
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future.
2015-12-10 | GSE61286 | GEO