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The EWS/FLI1 oncogenic transcription factor deregulates GLI1

Oncogene volume 27, pages 3282–3291 (2008)Cite this article

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.

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Acknowledgements

Support for this work was provided by the American Cancer Society (RPG-99-096-01), the National Cancer Institute (CA90666) and by the TJ Martell Foundation (WAM). We acknowledge Dr Evans Bailey for providing constructs and probes for northern blots and for technical assistance and of Dr Elizabeth Lawlor and Dr Michael Anderson for critical evaluation of the data.

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Authors and Affiliations

  1. Department of Dermatology, Stanford University School of Medicine, Palo Alto, CA, USA

    J P Zwerner

  2. Department of Pediatrics, Division of Hematology-Oncology, The Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA

    J Joo, K L Warner, L Christensen & W A May

  3. Department of Pathology, The Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA

    S Hu-Lieskovan & T J Triche

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  1. J P Zwerner
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Correspondence to W A May.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Zwerner, J., Joo, J., Warner, K. et al. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene 27, 3282–3291 (2008). https://doi.org/10.1038/sj.onc.1210991

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