EWS-FLI1 Perturbs MRTFB/YAP-1/TEAD Target Gene Regulation Inhibiting Cytoskeletal Autoregulatory Feedback in Ewing Sarcoma

Oncogene. 2017 Oct 26;36(43):5995-6005. doi: 10.1038/onc.2017.202. Epub 2017 Jul 3.

Abstract

Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells in vitro and in vivo, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cellular Reprogramming / genetics*
  • Chromatin / genetics
  • Cytoskeleton / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogene Protein c-fli-1 / genetics*
  • RNA-Binding Protein EWS / genetics*
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology
  • Signal Transduction / genetics

Substances

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