title: The EWS/FLI1 oncogenic transcription factor deregulates GLI1.
abstract: 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.
authors: Department of Dermatology, Stanford University School of Medicine, Palo Alto, CA, USA.
authors: J P
authors: JP
authors: Zwerner
authors: J
authors: J
authors: Joo
authors: K L
authors: KL
authors: Warner
authors: L
authors: L
authors: Christensen
authors: S
authors: S
authors: Hu-Lieskovan
authors: T J
authors: TJ
authors: Triche
authors: W A
authors: WA
authors: May
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010641:Phenotype; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology*; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
chemical_list: C106031:EWS-FLI fusion protein; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1