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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.
Afiliación
  • Gao Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • He XY; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Wu XS; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Huang YH; Genetics Program, Stony Brook University, Stony Brook, NY, USA.
  • Toneyan S; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Ha T; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Ipsaro JJ; School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Koo PK; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Joshua-Tor L; Howard Hughes Medical Institute, W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Bailey KM; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Egeblad M; Howard Hughes Medical Institute, W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Vakoc CR; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Nat Cell Biol ; 25(2): 298-308, 2023 02.
Article en En | MEDLINE | ID: mdl-36658219
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sarcoma de Ewing Límite: Child / Humans Idioma: En Revista: Nat Cell Biol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sarcoma de Ewing Límite: Child / Humans Idioma: En Revista: Nat Cell Biol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido