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

DOI: 10.1038/s41556-022-01060-1


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 > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > cis-regulatory elements
Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Egeblad lab
CSHL labs > Joshua-Tor lab
CSHL labs > Kinney lab
CSHL labs > Koo Lab
CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 19 January 2023
Date Deposited: 23 Jan 2023 17:28
Last Modified: 23 Jan 2023 17:28

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