| Literature DB >> 25453903 |
Nicolò Riggi1,2, Birgit Knoechel1,2,3,4, Shawn M Gillespie1,2,5, Bradley E Bernstein1,2,5, Miguel N Rivera1,2, Esther Rheinbay1,2, Gaylor Boulay1,2, Mario L Suvà1,2, Nikki E Rossetti1, Wannaporn E Boonseng1, Ozgur Oksuz1, Edward B Cook1, Aurélie Formey6, Anoop Patel5,7, Melissa Gymrek8,9,10, Vishal Thapar11, Vikram Deshpande12, David T Ting11, Francis J Hornicek13, G Petur Nielsen12, Ivan Stamenkovic6, Martin J Aryee1,2.
Abstract
The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.Entities:
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Year: 2014 PMID： 25453903 PMCID： PMC4492343 DOI： 10.1016/j.ccell.2014.10.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743