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

Cancer Cell. 2014 Nov 10;26(5):668-681. doi: 10.1016/j.ccell.2014.10.004. Epub 2014 Oct 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / metabolism
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly*
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Oncogene Proteins, Fusion / physiology*
  • Protein Binding
  • Proto-Oncogene Protein c-fli-1 / physiology*
  • RNA-Binding Protein EWS / physiology*
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / metabolism

Substances

  • EWS-FLI fusion protein
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS