The EWS/FLI1 oncogenic transcription factor deregulates GLI1

Oncogene. 2008 May 22;27(23):3282-91. doi: 10.1038/sj.onc.1210991. Epub 2007 Dec 17.


Ewing family tumors (EFT), classically Ewing's sarcoma and peripheral primitive neuroectodermal tumor, share a common class of tumor-specific fusion genes thought to be key mediators of tumor biology. Here we demonstrate that the most common Ewing's fusion, EWS/FLI1, produces transcriptional upregulation of GLI1 and its direct transcriptional target PATCHED1 in a model transformation system. This deregulation of GLI1 is common to other EWS/ets chimera and depends on the functional transcriptional regulatory domains. Inhibition of GLI1 via RNAi or via overexpression of endogenous inhibitors results in a reduction of EWS/FLI1 transformation activity. Activation of GLI1 appears to occur in a Hedgehog-independent fashion as blockade of Hedgehog signaling has only a modest effect on EFT cells. We present evidence that EWS/FLI1 upregulation of cMYC may play a role in the upregulation of GLI1 in EWS/FLI1-transformed NIH3T3 cells. Finally, we demonstrate that observations made in a model transformation system translate to an Ewing cellular background. EFT cell lines express GLI1 and PATCHED and this expression is EWS/FLI1 dependent. Inhibition of GLI1 expression via RNAi results in reduced anchorage-independent growth in an EFT cell line. GLI1 appears to be a transcriptionally deregulated target of EWS/FLI1 that mediates a portion of its tumorigenic phenotype.

Publication types

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

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Gene Expression Regulation, Neoplastic
  • Genes, myc / physiology
  • Hedgehog Proteins / physiology
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / physiology
  • Mice
  • NIH 3T3 Cells
  • Oncogene Proteins, Fusion / physiology*
  • Phenotype
  • Proto-Oncogene Protein c-fli-1 / physiology*
  • RNA-Binding Protein EWS
  • Sarcoma, Ewing / genetics
  • Transcription Factors / physiology
  • Transfection
  • Zinc Finger Protein GLI1


  • EWS-FLI fusion protein
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Transcription Factors
  • Zinc Finger Protein GLI1