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

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
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:	Gao, Yuan He, Xueyan Wu, Xiaoli Huang, Yuhan Toneyan, Shushan Ha, Taehoon Ipsaro, Jonathan J. Koo, Peter K Joshua-Tor, Leemor Egeblad, Mikala Vakoc, Christopher R.
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
Depositing User:	CSHL Elements
Date:	19 January 2023
Date Deposited:	23 Jan 2023 17:28
Last Modified:	29 Apr 2024 20:11
PMCID:	PMC10101761
Dataset ID:	GEO: GSE189418
URI:	https://repository.cshl.edu/id/eprint/40795

Actions (login required)

Administrator's edit/view item