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Analysis of ETS gene expression patterns uncovers novel ETS mediated gene silencing pathways in prostate cancers

ABSTRACT: Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes

ORGANISM(S): Homo sapiens

PROVIDER: GSE14206 | GEO | 2010/05/25

SECONDARY ACCESSION(S): PRJNA111331

REPOSITORIES: GEO

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Analysis of ETS gene expression patterns uncovers novel ETS mediated gene silencing pathways in prostate cancers

Project description:Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes In this study we show that deregulated expression of ETS factors with opposite functions is highly frequent in prostate cancer. Our study uncovers a previously unrecognized link between aberrant expression of ETS factors, deregulation of epigenetic pathways and silencing of tumor suppressor genes in prostate cancer and shows that partially distinct transcriptional programs are associated with different ETS gene expression patterns. The presence of distinct prostate cancer subgroups with different biological features may have important clinical implications and suggests that assessment of ETS expression levels might be useful to distinguish tumors with different clinical outcome.

2010-06-09 | E-GEOD-14206 | biostudies-arrayexpress

The ETS transcription factor ESE3 controls prostate epithelial cell differentiation

Project description:ETS transcription factors have recently emerged as important elements in the pathogenesis of prostate cancer (PCa). ETS gene rearrangements leading to over-expression of ETS factors, like ERG, ETV1 and ETV4, are found in about 50% of prostate tumors. While the oncogenic potential of translocated ETS has been demonstrated in several contexts, the impact of endogenously expressed ETS factors on prostate tumorigenesis has been largely overlooked. Here we show that the epithelial-specific ETS factor ESE3, which is normally expressed in basal prostate epithelial (PrE) cells and frequently down-regulated in prostate tumors, serves as gatekeeper to maintain cell differentiation and its down-regulation leads to the acquisition of mesenchymal, stem cell (SC) and tumorigenic properties. ESE3 exerts this function by regulating critical genes involved in the epithelial to mesenchymal transition (EMT) and cell “stemness” and maintaining the equilibrium between cell differentiation and proliferation. Loss of ESE3 may be an important step in prostate tumorigenesis. Keywords: prostate epithelial cells, prostate cancer, gene expression profiling, ETS genes, EMT, cancer stem cells

2012-06-05 | GSE23197 | 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]

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 | GSE83652 | GEO

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

2017-06-08 | GSE83651 | GEO

Loss of Function Mutations in ETS2 Repressor Factor (ERF) Reveal a Balance Between Positive and Negative ETS Factors Controlling Prostate Oncogenesis [22PC RNA-seq]

2017-06-08 | GSE83649 | GEO

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

2017-06-08 | GSE98809 | 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]

2017-06-08 | GSE98808 | GEO

A complex with poly(A) binding protein cytoplasmic 1 and EWS facilitates oncogenic ETS transcription factor function in prostate cells

Project description:The ETS transcription factor ERG is aberrantly expressed in approximately 50% of prostate tumors due to chromosomal rearrangements such as TMPRSS2/ERG. The ability of ERG to drive oncogenesis in prostate epithelial cells requires interaction with distinct co-activators, such as the RNA-binding protein EWS. Here, we find that ERG has both direct and indirect interactions with EWS, and the indirect interaction is mediated by the poly-A RNA-binding protein PABPC1. PABPC1 directly bound both ERG and EWS. ERG expression in prostate cells promoted PABPC1 localization to the nucleus and recruited PABPC1 to ERG/EWS binding sites in the genome. Knockdown of PABPC1 in prostate cells abrogated ERG-mediated phenotypes and decreased the ability of ERG to activate transcription. These findings define a complex including ERG and the RNA-binding proteins EWS and PABPC1 that represents a novel therapeutic target for ERG-positive prostate cancer and identify a novel nuclear role for PABPC1.

2023-11-06 | GSE226472 | GEO

Discovery of Non-ETS Gene Fusions using RNA Sequencing

Project description:Half of prostate cancers harbor gene fusions between TMPRSS2 and members of the ETS transcription factor family. To date little is known about the presence of non-ETS fusion events in prostate cancer. We employed next-generation transcriptome sequencing (RNA-Seq) in order to explore the whole transcriptome of 25 human prostate cancer samples for the presence of chimeric fusion transcripts. We generated more than 1 billion sequence reads and used a novel computational approach (FusionSeq) in order to identify novel gene fusion candidates with high confidence. In total, we discovered and characterized seven new cancer-specific gene fusions, two involving the ETS genes ETV1 and ERG, and five involving non-ETS genes such as CDKN1A (p21), CD9 and IKBKB (IKK-beta), genes known to exhibit key biological roles in cellular homeostasis or assumed to be critical in tumorigenesis of other tumor entities, as well as the oncogene PIGU and the tumor suppressor gene RSRC2. The novel gene fusions are found to be of low frequency but interestingly, the non-ETS fusions were all present in prostate cancer harboring the TMPRSS2-ERG gene fusion. Future work will focus on determining if the ETS rearrangements in prostate cancer are associated or directly predispose to a rearrangement prone phenotype.

| phs000310 | dbGaP

ELF1 expression in prostate cells reduces oncogenic ETS functions and promotes senescence and sensitivity to chemotherapy through distinct gene expression programs [RNA-seq]

Project description:Aberrant overexpression of oncogenic ETS factors through chromosomal rearrangments is the most common genomic event in primary prostate tumor and these factors have been well studied. Loss of ELF1, another ETS transcription factor family member, is a common event in prostate cancer, but the function of ELF1 has not been described within the prostate. Studies of ELF1 in different tissue types has determined that it can be important for oncogeneis or tumor suppression. Here, we show that ELF1 is a novel prostate tumor suppressor by hindering oncogenic ETS function at cell migration related genes, but also that ELF1 has the ability to regulate senescence and chemotherapy resistance. Next generation sequencing was used to determine gene expression changes in RWPE-1 cells upon addition of an oncogenic ETS factor and then with the loss of ELF1 through an shRNA knockdown. Genomic binding locations were also determined for ELF1 and ERG, through ChIP-seq to identify any cobound or unique regions. The combination of this data indicates that ELF1 repressed migration related genes which ERG activates, but ELF1 also uniquely binds genes related to cell senescence and activates their transcription. There, these data indicate a novel tumor suppressive mechanism for ELF1 within the prostate and better characterizes its function within this cell type.

2018-07-01 | GSE113485 | GEO

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