تقرير
ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation
| العنوان: | ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation |
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| المؤلفون: | Gao, Yuan, He, Xue-Yan, Wu, Xiaoli S, Huang, Yu-Han, Toneyan, Shushan, Ha, Taehoon, Ipsaro, Jonathan J, Koo, Peter K, Joshua-Tor, Leemor, Bailey, Kelly M, Egeblad, Mikala, Vakoc, Christopher R |
| سنة النشر: | 2023 |
| المجموعة: | Cold Spring Harbor Laboratory: CSHL Institutional Repository |
| مصطلحات موضوعية: | bioinformatics, DNA, RNA structure, function, modification, diseases & disorders, genetics & nucleic acid processing, genomics and proteomics, Investigative techniques and equipment, neoplasms, cell line, cell types, cell types and functions, cis-regulatory elements, CRISPR-Cas9, genes, structure and function, genes: types, oncogene, organs, tissues, organelles, sarcoma |
| الوصف: | The EWS-FLI1 fusion oncoprotein deregulates transcription to initiate the paediatric cancer Ewing sarcoma. Here we used a domain-focused CRISPR screen to implicate the transcriptional repressor ETV6 as a unique dependency in this tumour. Using biochemical assays and epigenomics, we show that ETV6 competes with EWS-FLI1 for binding to select DNA elements enriched for short GGAA repeat sequences. Upon inactivating ETV6, EWS-FLI1 overtakes and hyper-activates these cis-elements to promote mesenchymal differentiation, with SOX11 being a key downstream target. We show that squelching of ETV6 with a dominant-interfering peptide phenocopies these effects and suppresses Ewing sarcoma growth in vivo. These findings reveal targeting of ETV6 as a strategy for neutralizing the EWS-FLI1 oncoprotein by reprogramming of genomic occupancy. |
| نوع الوثيقة: | report |
| اللغة: | unknown |
| العلاقة: | Gao, Yuan, He, Xue-Yan, Wu, Xiaoli S, Huang, Yu-Han, Toneyan, Shushan, Ha, Taehoon, Ipsaro, Jonathan J, Koo, Peter K, Joshua-Tor, Leemor, Bailey, Kelly M, Egeblad, Mikala, Vakoc, Christopher R (January 2023) ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nature Cell Biology. ISSN 1465-7392 (Public Dataset) |
| DOI: | 10.1038/s41556-022-01060-1 |
| الإتاحة: | https://doi.org/10.1038/s41556-022-01060-1Test https://repository.cshl.edu/id/eprint/40795Test/ https://www.ncbi.nlm.nih.gov/pubmed/36658219Test |
| رقم الانضمام: | edsbas.180F53CC |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41556-022-01060-1 |
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