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An interaction with Ewing's sarcoma breakpoint protein EWS defines the subset of ETS factors rearranged in prostate cancer

ABSTRACT: ERG activates prostate cancer specific gene expression program by recruiting RNA binding protein EWS to ETS-AP1 and GGAA microsatellite enhancers

ORGANISM(S): Homo sapiens

PROVIDER: GSE73616 | GEO | 2016/10/28

SECONDARY ACCESSION(S): PRJNA297431

REPOSITORIES: GEO

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An interaction with Ewing's sarcoma breakpoint protein EWS defines the specific oncogenic mechanism of ETS factors rearranged in prostate cancer

Project description:ERG activates prostate cancer specific gene expression program by recuriting RNA binding protein EWS

2016-10-28 | GSE81493 | GEO

A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [RNA-Seq]

Project description:Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. EWS/FLI regulates myriad genes required for Ewing sarcoma development. EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro, and these sequences provide EWS/FLI-mediated activation to reporter constructs, suggesting that they function as EWS/FLI-response elements. Genomic GGAA-microsatellites are highly variable and polymorphic. Current data suggest that there is an optimal “sweet-spot” GGAA-microsatellite length (of 18-26 GGAA repeats) that confers maximal EWS/FLI-responsiveness to target genes, but the mechanistic basis for this was not known. We now demonstrate the absolute necessity of an EWS/FLI-bound GGAA-microsatellite in regulation of the NR0B1 gene, as well as for Ewing sarcoma proliferation and oncogenic transformation. Biochemical studies, using recombinant Δ22 (a version of EWS/FLI containing only the FLI portion) demonstrated a stoichiometry of one Δ22-monomer binding to every two consecutive GGAA-repeats on shorter GGAA-microsatellite sequences. Surprisingly, the affinity for Δ22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasureable, when the size of the GGAA-microsatellite was increased to the “sweet-spot” length. In contrast, a fully-functional EWS/FLI mutant (Mut9) that retains approximately half of the EWS portion of the fusion showed low affinity for smaller GGAA-microsatellites, but instead significantly increased its affinity at “sweet-spot” microsatellite lengths. Single-gene ChIP and genome-wide ChIP-seq and RNA-seq studies extended these findings to the in vivo setting. Taken together, these data demonstrate the absolute requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unsuspected novel role for the EWS portion of the EWS/FLI fusion in binding to optimal-length GGAA-microsatellites.

2017-10-22 | GSE94502 | GEO

A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [ChIP-Seq]

2017-10-22 | GSE94480 | GEO

ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation

Project description:we report a synthetic lethality of ETV6 and EWS-FLI1 in ewing sarcome that is imposed by ETV6 antagonize EWS-FLI1 from particular GGAA microsatellite sites

2022-10-18 | GSE189418 | GEO

A functional liaison between E2F and the aberrant ETS oncogene EWS/FLI1 in Ewing's sarcoma

Project description:Translocations of ETS transcription factors are driver mutations in diverse cancers. We investigated the genomic network of the ETS fusion EWS/FLI1 in Ewing's sarcoma (ESFT) as a model of ETS-driven tumorigenesis. ChIP-Seq and transcriptional analysis identified E2F3 as a principle co-factor of EWSFLI1 defining functionally distinct gene sets. While EWS/FLI1 binding independent of E2F3 predominantly associated with repressed differentiation genes, significant co-localization with E2F3 was discovered at proximal promoters of activated growth-related genes. Thus, EWS/FLI1 promotes oncogenesis by simultaneously perturbing differentiation state and augmenting the expression of genes co-regulated by E2F3. Integration of additional E2F3 and ERG localization data from prostate cancer containing TMPRSS2/ERG verified that the ETS-E2F module is also found in prostate cancer and may be of general relevance to ETS driven cancers. Timecourse with 6 timepoints of a doxicyclin inducible EWS-FLI1 knockdown in the A673 Ewing's Sarcoma celline

2013-07-01 | E-GEOD-27524 | biostudies-arrayexpress

An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

Project description: Not available

| S-EPMC5123826 | biostudies-literature

A functional liaison between E2F and the aberrant ETS oncogene EWS/FLI1 in Ewing's sarcoma

2013-07-01 | GSE27524 | GEO

Transcription profiling of human mesenchymal progenitor stem cells overexpressing EWS/ETS protein

Project description:We have examined the biological effect of EWS/ETS in human MPCs using UET-13 cells that are obtained by prolonging the lifespan of human bone marrow stromal cells using the retroviral transgenes hTERT and E7. By exploiting tetracycline-inducible systems for expressing EWS/ETS (EWS/FLI1 and EWS/ERG), we investigated candidates for genes whose expression is regulated by EWS/ETS in human MPCs. Experiment Overall Design: A change of expression profiles in the presence of EWS/ETS using Affymetrix HG-U133 Plus 2.0 (GPL570).

2008-06-16 | E-GEOD-8665 | biostudies-arrayexpress

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

Effect of RREB1 knockdown using siRNA in A673 Ewing sarcoma cells (RNA-seq)

Project description:Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed EwS cases had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer, and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential, and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

2023-10-23 | GSE220780 | GEO

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