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CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [ChIP-seq]

ABSTRACT: Ewing sarcoma is characterized by a chromosomal translocation resulting in the fusion protein EWSR1-FLI1. To identify small molecules that selectively impair the oncogenic transcriptional program enacted by EWS-FLI1 we employed a novel phenotypic screen. Our screening hits were enriched for inhibitors of cyclin dependent kinase 8/19. Inhibition of CDK8/19 resulted in a proliferation defect in Ewing sarcoma cells and a reduction in growth of Ewing sarcoma xenografts. We performed a genome wide pooled CRISPR screen that suggested that small molecule inhibition of CDK8/19 acted in a gain-of-function manner that did not replicate the effects of CDK8/19 genetic knockout. Through biochemical studies and chromatin profiling, we discovered that CDK8/19 inhibitors act through a novel trapping mechanism in which the inhibitor prevents dissociation of the CDK8 kinase from core Mediator. This mechanism has broad implications for the development of small molecules to target transcriptional regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302426 | GEO | 2026/07/09

REPOSITORIES: GEO

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CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [CRISPR]

Project description:Ewing sarcoma is characterized by a chromosomal translocation resulting in the fusion protein EWSR1-FLI1. To identify small molecules that selectively impair the oncogenic transcriptional program enacted by EWS-FLI1 we employed a novel phenotypic screen. Our screening hits were enriched for inhibitors of cyclin dependent kinase 8/19. Inhibition of CDK8/19 resulted in a proliferation defect in Ewing sarcoma cells and a reduction in growth of Ewing sarcoma xenografts. We performed a genome wide pooled CRISPR screen that suggested that small molecule inhibition of CDK8/19 acted in a gain-of-function manner that did not replicate the effects of CDK8/19 genetic knockout. Through biochemical studies and chromatin profiling, we discovered that CDK8/19 inhibitors act through a novel trapping mechanism in which the inhibitor prevents dissociation of the CDK8 kinase from core Mediator. This mechanism has broad implications for the development of small molecules to target transcriptional regulation.

2026-07-10 | GSE305845 | GEO

CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [CUT&RUN]

2026-07-09 | GSE302425 | GEO

CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [ATAC-seq]

2026-07-09 | GSE302424 | GEO

CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [RNA-Seq]

2026-07-10 | GSE304126 | GEO

Neo-peptides identification in Ewing sarcoma cell lines using proteomics approach

Project description:Ewing sarcoma (EwS) is an adolescent and young adult sarcoma characterized by chromosome translocations between members of the FET family of RNA binding proteins and members of the ETS family of transcription factors, the most frequent fusion being EWS-FLI1. EWS-FLI1 acts as a pioneer factor, creating de novo enhancers and activating genes located in the vicinity of EWS-FLI1-bound microsatellite sequences. recent results from our lab indicate that EWS-FLI1, which activates transcription through binding to the DNA at specific sites, can generate fully novel, unconventional transcription units in regions of the genome that are fully quiescent in normal cells (manuscript in preparation). The hypothesis of the project is that the open reading frames (ORFs) of these transcripts may encode peptides presented at the cell surface by HLA class I molecules and hence be recognized as non-self by the immune system. The aim of this study is to detect Ewing-specific neo-peptides/proteins using proteomics approach.

2022-05-12 | PXD027309 | Pride

High-throughput RNAi cell viability screen to identify selective targets for EWS-FLI1 positive Ewing sarcoma

Project description:We have performed a high-throughput RNA interference screen to identify targets inhibiting EWS-FLI1 driven cell proliferation in Ewing sarcoma cells. EWS-FLI1 expressing A673 Ewing sarcoma cells were screened both in presence and absence of EWS-FLI1 shRNA induction with druggable siRNA library. Leucine rich repeats and WD repeat Domain containing 1 (LRWD1) targeting siRNA pool was the strongest anti-proliferative hit identified only in presence of EWS-FLI1. Validation experiments confirmed the anti-proliferative effect of LRWD1 depletion especially in EWS-FLI1 expressing cells. Functional analysis of differentially expressed genes in LRWD1 depleted Ewing sarcoma cells showed over-representation of connective tissue development, cell projection morphogenesis and neuronal processes.

2018-09-16 | GSE73092 | GEO

Genome-wide chromatin analysis of Ewing sarcoma (ChIP-seq)

Project description:We show that EWS-FLI1, an aberrant transcription factor responsible for the pathogenesis of Ewing sarcoma, reprograms gene regulatory circuits by directly inducing or directly repressing enhancers. At GGAA repeats, which lack regulatory potential in other cell types and are not evolutionarily conserved, EWS- FLI1 multimers potently induce chromatin opening, recruit p300 and WDR5, and create de novo enhancers. GGAA repeat enhancers can loop to physically interact with target promoters, as demonstrated by chromosome conformation capture assays. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors and abrogating p300 recruitment. ChIP-seq for of 4 histone modifications (H3K27ac, H3K4me1, H3K4me3 and H3K27me3), FLI1, p300, WDR5, ELF1 and GABPA in primary Ewing sarcomas, Ewing sarcoma cell lines (A673 and SKMNC cells), and mesenchymal stem cells (MSC). EWS-FLI1 was knocked down in Ewing sarcoma cell lines with lentiviral shRNAs (shFLI1 and shGFP control). EWS-FLI1 was expressed in MSCs with lentiviral expression vectors (pLIV EWSFLI1 or pLIV empty vector control). * Raw data not provided for the MSC and Primary Ewing sarcoma samples. *

2014-10-30 | E-GEOD-61944 | biostudies-arrayexpress

Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm

Project description:Ewing sarcoma is a malignant small round blue cell tumor of bones and soft tissues, predominantly affecting children, adolescents and young adults. Ewing sarcoma is caused by chromosomal translocations that generate aberrant chimeric transcription factors, most frequently EWSR1::FLI1. Ewing sarcomas exhibit features of both neural and mesenchymal cells. The cell of origin of Ewing sarcoma and the mechanisms of EWSR1::FLI1-driven cell transformation are the subjects of long-standing debates, largely due to the absence of a representative animal model. By developing a robust Ewing sarcoma model in zebrafish, we provide evidence for a neural crest origin of this cancer. We show that neural crest-derived cells (NCCs) uniquely tolerate expression of the human EWSR1::FLI1 oncofusion protein in vivo and that targeted expression of the oncofusion in NCCs is sufficient to generate Ewing sarcoma tumors. In the trunk, EWSR1::FLI1 reprogrammed NCCs to a mesoderm-like state, including upregulation of the early mesoderm specifier tbxta (Brachyury/T) and mesenchymal genes pdgfra, twist1a, and prrx1a. Mesodermal reprogramming of trunk neural crest was evident by the ability of EWSR1::FLI1-expressing cells to induce ectopic fins throughout the body. Single-nucleus analysis of RNA expression and chromatin accessibility, combined with genome-wide profiling of EWSR1::FLI1 binding, revealed that EWSR1::FLI1 targets single GGAA-containing ETS sites in mesodermal developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation, also binding to GGAA repeats in established tumors. These findings show that EWSR1::FLI1 hijacks normal ETS-dependent developmental pathways in embryonic NCCs to drive initiation of Ewing sarcoma.

2025-10-09 | GSE306234 | GEO

Origin of Ewing sarcoma by embryonic reprogramming of neural crest to mesoderm

2025-10-09 | GSE280398 | GEO

Expression data from the inducible expression of EWS-FLI1 (EF) in embryoid bodies

Project description:Oncogenic transformation in Ewing sarcoma tumors is driven by the fusion oncogene EWS-FLI1. The inducible expression of EWS-FLI1 (EF) in embryoid bodies, or collections of differentiating stem cells, generates cells with properties of Ewing sarcoma tumors, including characteristics of transformation. These cell lines exhibit anchorage-independent growth, a lack of contact inhibition and a strong Ewing sarcoma gene expression signature. These cells also demonstrate a requirement for the persistent expression of EWS-FLI1 for cell survival and growth. We used microarrays to detail the effects of doxycycline-inducible expression of EWS-FLI1 on the gene expression signature of cells derived from differentiating stem cells, or embryoid bodies. Triplicate biological replicates were collected and analyzed.

2015-12-31 | E-GEOD-64686 | biostudies-arrayexpress

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