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Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis

Oncogene volume 27, pages 3856–3864 (2008)Cite this article

Abstract

Mutations in the Hedgehog signaling pathway is responsible for the formation of various cancers, including some forms of basal cell carcinoma (BCC). Uncontrolled Hedgehog signaling leads to overexpression of the zinc-finger Gli transcription factors, among which Gli2 plays a central role. We found that high Gli2 expression induced the concomitant high expression of the caspase 8 inhibitor, cFlip, and thereby counteracts death-ligand-mediated apoptosis. By investigating the cFlip promoter, Gli2 binding sites were identified and confirmed. Gli2 gene silencing by RNA interference broke the apoptosis resistance via cFlip downregulation. The direct functional connection between Gli2 and cFlip was not only demonstrated in a keratinocytic cell line but also in BCC tissue. As cFlip and Bcl-2 are highly expressed in BCCs, as a consequence of high Gli2 expression, this may explain the marked resistance of the tumor to the extrinsic and intrinsic apoptotic pathway. We could now demonstrate that Gli2 gene silencing in BCC tissues made the tumor sensitive to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-mediated cell death by downregulating cFlip. As Gli2 silencing does not only downregulate cFlip, but also Bcl-2, Gli2 could be a key target for a novel therapeutic approach in tumors with dysregulated Hedgehog signaling.

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Acknowledgements

We are grateful to Dr Bernd Rattenbacher for his technical and intellectual support and to Dr Georg Funk for his help in the statistical analysis. We thank Professor SA Buechner for providing BCC biopsies. This work was supported by the Swiss National Science Funds Grant no. 3100A0-111368/1 and the Oncosuisse Grant no. 01630-02-2005. EK was supported by the Freiwilligen Akademischen Gesellschaft Basel.

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  1. E Kump and J Ji: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedicine, Institute for Medical Microbiology, University of Basel, Basel, Petersplatz, Switzerland

    E Kump, J Ji, M Wernli & P Erb

  2. Department of Dermatology, University Hospital Basel, Basel, Switzerland

    P Häusermann

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  1. E Kump
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  2. J Ji
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  3. M Wernli
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  4. P Häusermann
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  5. P Erb
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Correspondence to P Erb.

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

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Kump, E., Ji, J., Wernli, M. et al. Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene 27, 3856–3864 (2008). https://doi.org/10.1038/onc.2008.5

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