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Integrative sequencing reveals alterations in untreated and castration-resistant prostate cancer

ABSTRACT: We conducted an integrative sequencing of genomic, transcriptomic and DNA methylation changes in 28 untreated (PC) and 13 castration-resistant prostate cancers (CRPC). We wanted to search for previously unannotated transcripts from the RNA-sequencing data. Transcriptome assembly uncovered 128 previously unannotated prostate cancer-associated transcripts. Trans-acting correlation analysis associated the expression of several TPCATs with prostate cancer-associated transcriptional regulators, such as ERG or AR. The strongest positive correlation was observed between ERG and transcript TPCAT-10-36067 that was expressed in a subset of PCs and CRPCs as well as ETV4-positive PC-3 and ERG-positive VCaP cells. We suppressed the expression of TPCAT-10-36067 with three different siRNAs in PC-3 cells, and studied the changes in the genome-wide expression patterns of the cell line using expression arrays. Gene Ontology enrichment analysis indicated that cell cycle, mitosis and Aurora signaling were the most extensively affected processes. Experimental assay showed that the siRNA suppression of TPCAT-10-36067 had a dramatic effect on the growth, invasiveness, and rate of apoptosis of prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48211 | GEO | 2016/06/05

SECONDARY ACCESSION(S): PRJNA209207

REPOSITORIES: GEO

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Gene expression changes upon knockdown or over-expression of the ETS gene ETV4 in prostate cancer cell lines

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

Gene expression changes upon knockdown or over-expression of the ETS gene ETV4 in prostate cancer cell lines

2011-03-25 | GSE21209 | GEO

Integrative sequencing reveals alterations in untreated and castration resistant prostate cancer

Project description:We report the integrative sequencing of genomic, transcriptomic and DNA methylation changes in 28 untreated (PC) and 13 castration resistant prostate cancers (CRPC). AR, TGF-? and WNT signaling pathways were altered in CRPCs. We identified two new fusion genes, TMPRSS2-SKIL and DOT1L-HES6. Fusion analysis in an independent cohort validated SKIL as a recurrent 3Â’ fusion partner and oncogene in prostate cancer. The HES6 fusion was found in an AR-negative CRPC, and HES6 overexpression in vitro led to androgen independent growth. A distinct DNA methylation signature was found for CRPC. Transcriptome assembly uncovered 128 previously unannotated prostate cancer associated transcripts, including the ERG regulated transcript TPCAT-10-36067 whose knockdown had a dramatic effect on the growth, invasiveness, and rate of apoptosis of prostate cancer cells.

| EGAS00001000526 | EGA

Human PC-3 prostate cancer cells: Control (shNTC; non-target shRNA) vs. shETV4 knock down (shETV4)

Project description:Transcriptional profiling of human PC-3 prostate cancer cells lentivirally infected with non-target control (NTC) short hairpin (sh)RNA comparing with lentivirally shRNA mediated human ETV4 knock-down. Cells were either cultured for 24 hours at 20% oxygen tension or 0.2% oxygen. Goal was to determine (i) genes affected by hypoxia in PC-3 NTC cells and (ii) identification of hypoxically induced genes requiring ETV4 for hypoxic regulation.

2011-12-06 | GSE32385 | GEO

Human PC-3 prostate cancer cells: Control (shNTC; non-target shRNA) vs. shETV4 knock down (shETV4)

2011-12-06 | E-GEOD-32385 | biostudies-arrayexpress

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. [RNA-seq]

Project description:Chromosomal rearrangements resulting in the fusion of TMRPSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

2018-08-02 | GSE110656 | GEO

Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.[ChIP-seq]

2018-08-02 | GSE110655 | GEO

Aberrant stabilized ETV4 expression cooperates with loss of p53 to promote invasive prostate carcinoma

Project description:Chromosomal translocations or upregulations involving ETS transcription factor are frequent events in prostate cancer pathogenesis and significantly co-occurrence with p53 or PTEN loss. Caused by the low stabilities of ETS proteins in cytosol, mouse models with aberrant expression of wild type ETS transcription factors had subtle phenotypes and only drive prostate cancer progression in the setting of Pten loss. Here we show that prostate specific aberrant expression of mutated ETV4 (V70P71D72-AAA, ETV4-AAA), which is resistence to COP1 mediated protein degradation, results in more stabilized ETV4 protein in mouse prostate. We found that ETV4-AAA mice develop marked prostatic intraepithelial neoplasia (mPin) and p53-dependent cell senescence within 2 weeks, but without tumor development when aged. Interestingly, ETV4-AAA positive cells reduce dramatically in a PTEN loss background, which means that there is no cooperation between ETV4-AAA and PTEN loss. Aberrant ETV4-AAA expression promotes progression of mPin to prostatic adenocarcinoma in a Tp53 deficiency or haploinsufficiency background. In contrast to PTEN loss induced mouse prostate cancers which loss NKX3.1 expression and resistant to castration therapy, these ETV4-AAA tumor cells well maintain AR and NKX3.1 expression and are sensitive to castration therapy.

2021-01-01 | GSE130311 | GEO

Loss of Function Mutations in ETS2 Repressor Factor (ERF) Reveal a Balance Between Positive and Negative ETS Factors Controlling Prostate Oncogenesis [Organoids ChIP-Seq]

Project description:Half of prostate cancers are caused by a gene-fusion that enables androgens to drive expression of the normally silent ETS transcription factor ERG in luminal prostate cells1-4. Recent prostate cancer genomic landscape studies5-10 have reported rare but recurrent point mutations in the ETS repressor ERF11. Here we show these ERF mutations cause decreased protein stability and ERF mutant tumours are mostly exclusive from those with ERG fusions. ERF loss recapitulates the morphologic and phenotypic features of ERG gain in primary mouse prostate tissue, including expansion of the androgen receptor (AR) transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of PTEN loss that yields oncogenic activity by ERG. Furthermore, in a human prostate cancer model of ERG gain and wild-type ERF, ChIP-seq studies indicate that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites. Consistent with a competition model, ERF loss rescues ERG-positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by displacement of ERF and raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

2017-06-08 | GSE98808 | GEO

Loss of Function Mutations in ETS2 Repressor Factor (ERF) Reveal a Balance Between Positive and Negative ETS Factors Controlling Prostate Oncogenesis [VCaP RNA-Seq]

2017-06-08 | GSE83652 | GEO

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