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

Kump, E. and Ji, J. and Wernli, M. and Häusermann, P. and Erb, P.. (2008) Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene, Vol. 27. pp. 3856-3864.

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Official URL: http://edoc.unibas.ch/dok/A6006656

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie und Venerologie (Itin)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Spezialfächer (Klinik) > Dermatologie USB > Dermatologie und Venerologie (Itin)
UniBasel Contributors:Häusermann, Peter
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Macmillan
ISSN:0950-9232
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:11 Oct 2012 15:32
Deposited On:11 Oct 2012 15:29

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