EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.

Cancer Cell
Authors
Keywords
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.

Year of Publication
2014
Journal
Cancer Cell
Volume
26
Issue
5
Pages
668-81
Date Published
2014 Nov 10
ISSN
1878-3686
URL
DOI
10.1016/j.ccell.2014.10.004
PubMed ID
25453903
PubMed Central ID
PMC4492343
Links
Grant list
U54 HG006991 / HG / NHGRI NIH HHS / United States
T32 HL007574 / HL / NHLBI NIH HHS / United States
T32 HL007574-30 / HL / NHLBI NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States
K12 CA087723 / CA / NCI NIH HHS / United States