ChIP-seq of A673 Ewing sarcoma cells using a specific anti-MYBL2 antibody
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA490874 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7829657.fastq.gz | Fastqsanger.gz | |||
| SRR7829658.fastq.gz | Fastqsanger.gz |
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Project description:Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here we demonstrate in the Ewing sarcoma model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response. We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls transcription of MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Genetic interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased proliferation and tumorigenicity of Ewing sarcoma cells. Combined RNA- and ChIP-seq experiments identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments high MYBL2 levels sensitized Ewing sarcoma cells for inhibition of its activating cyclin dependent kinase, CDK2, in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.
2019-08-16 | GSE119971 | GEO
Project description:EWS-FLI-1 was silenced by an shRNA in A673 Ewing sarcoma cells and the resulting alterations in the secretome was analyzed by GeLC-MS/MS approach (six gel slices for each sample, luciferase shRNA-expressing cell secretome as control)
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Project description:STAG2, a member of cohesin, is one of the most recurrently mutated genes in human cancer. Here, we investigated STAG2 function in the context of Ewing sarcoma, an aggressive bone tumor driven by EWS-FLI1 oncogene chimeric transcription factor. A673 Ewing sarcoma cell line was trasfected with siCT or 2 different siRNA targetting STAG2 during 72h and CTCF HiChIP experiments were preformed for each conditions. Analyses of HiChIP data show that STAG2 knowck-down alters CTCF-anchored loop extrusion.
2021-04-29 | GSE156650 | GEO
Project description:This dataset examined the effect of RUVBL1 knockout in A673 Ewing sarcoma cells. The gene expression profiling (RNA-seq) and the chromatin targeting of MYC (ChIP-seq) are reported.
2023-03-27 | GSE182378 | GEO
Project description:In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is expressed at low levels in Ewing sarcoma cells and primary tumors and is downregulated by the EWS/FLI1 oncoprotein characteristic of these tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we show that LOX displays tumor suppressor activities. Interestingly, we show that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Finally, we show that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significant deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based in the administration of LOX propeptide or functional analogues could be useful in the treatment of this devastating paediatric cancer. A673 cells derived from Ewing sarcoma were genetically enginereed to express LOX-PP upon doxycycline stimulation (72 hours). Three independent experiments from control cells and three independent experiments from A673 cells expressing LOX-PP were done. Gene expression profile in A673 cells expressing LOX-PP vs control cells were compared.
2013-12-31 | E-GEOD-46407 | biostudies-arrayexpress
Project description:Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here we demonstrate in the Ewing sarcoma model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response. We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls transcription of MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Genetic interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased proliferation and tumorigenicity of Ewing sarcoma cells. Combined RNA- and ChIP-seq experiments identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments high MYBL2 levels sensitized Ewing sarcoma cells for inhibition of its activating cyclin dependent kinase, CDK2, in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.
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Project description:This study looks at the transcriptional profile of LSD2 knockdown in A673 Ewing sarcoma cells.
2019-08-29 | GSE126275 | GEO
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA
2014-05-01 | E-GEOD-56900 | biostudies-arrayexpress
Project description:Comparison of gene expression profile of Ewing sarcoma cells which have an exchange of the endogenous EWS/FLI1 to either wild-type or a turnover-deficient mutant EWS/FLI1. Most target genes are saturated as only a few target genes are soly driven by increasing protein amount. The effect of a stable EWS/FLI1 mutant on global gene expression was evaluated in A673 Ewing sarcoma cells.
2016-11-16 | GSE81018 | GEO
Project description:An increasing number of cancer-associated mutations have been identified. Unfortunately, little therapy today exploits these tumor-specific genetic lesions. Often, the resulting oncoproteins have been intractable to easy manipulation with current small molecule screening approaches. To overcome this impasse, we developed an expression-based approach to small molecule library screening. We applied this platform to the discovery of modulators of the activity of EWS/FLI, the Ewing sarcoma associated oncoprotein. Cytarabine (ARA-C) was identified as the top hit in a small molecule library screen. ARA-C modulates EWS/FLI by decreasing EWS/FLI protein level and has striking effects on cellular viability and transformation in in vitro and in vivo models of Ewing sarcoma. With poor outcomes for patients with relapsed Ewing sarcoma and the well established safety profile of ARA-C, clinical trials testing ARA-C in Ewing sarcoma are warranted. Expression data was created for A673 cells treated with ARA-C and two other compounds used to treat Ewing sarcoma (Puromycin and Doxorubicin) at two doses (EC50 and 2xEC50) and three time points (24 hours, 3 days, and 5 days). Experiment Overall Design: A673 cells were treated with ARA-C (at doses of EC50 and 2xEC50) or vehicle in triplicate and expression profiled at 24 hours, 3 days, and 5 days. To exclude the possibility that ARA-C's modulation of the EWS/FLI signature was simply a non-specific response to treatment with all cytotoxic agents, we asked whether other compounds known to kill Ewing sarcoma cells (Doxorubicin and Puromycin) would induce the EWS/FLI off genome-wide expression pattern. A673 cells were treated with Doxorubicin and Puromycin (at doses of EC50 and 2xEC50) and expression profiled at 24 hours, 3 days, and 5 days.
2008-11-22 | E-GEOD-6930 | biostudies-arrayexpress