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

Yuan Gao; Xue Yan He; Xiaoli S. Wu; Yu Han Huang; Shushan Toneyan; Taehoon Ha; Jonathan J. Ipsaro; Peter K. Koo; Leemor Joshua-Tor; Kelly M. Bailey; Mikala Egeblad; Christopher R. Vakoc

doi:10.1038/s41556-022-01060-1

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

Yuan Gao, Xue Yan He, Xiaoli S. Wu, Yu Han Huang, Shushan Toneyan, Taehoon Ha, Jonathan J. Ipsaro, Peter K. Koo, Leemor Joshua-Tor, Kelly M. Bailey, Mikala Egeblad, Christopher R. Vakoc

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12 Scopus citations

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.

Original language	English
Pages (from-to)	298-308
Number of pages	11
Journal	Nature Cell Biology
Volume	25
Issue number	2
DOIs	https://doi.org/10.1038/s41556-022-01060-1
State	Published - Feb 2023

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title = "ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation",

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.",

author = "Yuan Gao and He, {Xue Yan} and Wu, {Xiaoli S.} and Huang, {Yu Han} and Shushan Toneyan and Taehoon Ha and Ipsaro, {Jonathan J.} and Koo, {Peter K.} and Leemor Joshua-Tor and Bailey, {Kelly M.} and Mikala Egeblad and Vakoc, {Christopher R.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41556-022-01060-1",

language = "English",

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AU - Gao, Yuan

AU - He, Xue Yan

AU - Wu, Xiaoli S.

AU - Huang, Yu Han

AU - Toneyan, Shushan

AU - Ha, Taehoon

AU - Ipsaro, Jonathan J.

AU - Koo, Peter K.

AU - Joshua-Tor, Leemor

AU - Bailey, Kelly M.

AU - Egeblad, Mikala

AU - Vakoc, Christopher R.

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N2 - 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.

AB - 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.

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

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