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)
Abstract
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.
Item Type: |
Paper
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Subjects: |
bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > cis-regulatory elements Investigative techniques and equipment > CRISPR-Cas9 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > sarcoma |
CSHL Authors: |
![](http://repository.cshl.edu/util/irpics/gao_yuan.jpg) Gao, Yuan![](http://repository.cshl.edu/util/irpics/he_xueyan.jpg) He, Xueyan![](http://repository.cshl.edu/util/irpics/wu_xiaoli.jpg) Wu, Xiaoli![](http://repository.cshl.edu/util/irpics/huang_yuhan.jpg) Huang, Yuhan![](http://repository.cshl.edu/util/irpics/toneyan_shushan.jpg) Toneyan, Shushan![](http://repository.cshl.edu/util/irpics/ha_taehoon.jpg) Ha, Taehoon![](http://repository.cshl.edu/util/irpics/ipsaro_jonathan.jpg) Ipsaro, Jonathan J.![](http://repository.cshl.edu/util/irpics/koo_peter.jpg) Koo, Peter K![](http://repository.cshl.edu/util/irpics/joshua_tor_leemor.jpg) Joshua-Tor, Leemor![](http://repository.cshl.edu/util/irpics/egeblad_mikala.jpg) Egeblad, Mikala![](http://repository.cshl.edu/util/irpics/vakoc_christopher_r.jpg) Vakoc, Christopher R.
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Communities: |
CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Egeblad lab CSHL labs > Joshua-Tor lab CSHL labs > Kinney lab CSHL labs > Koo Lab CSHL labs > Vakoc lab School of Biological Sciences > Publications |
SWORD Depositor: |
CSHL Elements
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Depositing User: |
CSHL Elements
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Date: |
19 January 2023 |
Date Deposited: |
23 Jan 2023 17:28 |
Last Modified: |
29 Apr 2024 20:11 |
PMCID: |
PMC10101761 |
Dataset ID: |
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URI: |
https://repository.cshl.edu/id/eprint/40795 |
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