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  • Original Article
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Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

Oncogene volume 26, pages 4489–4498 (2007)Cite this article

Abstract

The Hedgehog pathway transcription factor Gli1 induces transformation of epithelial cells via induction of Snail, a repressor of E-cadherin (E-cad). E-cad is normally complexed with β-catenin at the cell membrane. Loss of E-cad during developmental epithelial–mesenchymal transitions can switch β-catenin from its role at adherens junctions to its role in nuclear transcription. During tumorigenesis it is unclear which pathways trigger this switch. In the current study, gain- and loss-of-function approaches identified E-cad as a selective inhibitor of transformation by Gli1, and Snail knockdown was rescued by downregulation of E-cad. Gli1 induced relocalization of β-catenin from the cell membrane to the nucleus. The ability of wild-type or mutant alleles of E-cad to modulate transformation by Gli1 correlated with their ability to regulate localization of β-catenin. Inhibition of Wnt-β-catenin signaling by dominant negative Tcf4 selectively blocked in vitro transformation by Gli1. In Gli1-transgenic mice, infiltrating skin tumor cells expressed active, unphosphorylated β-catenin. Our studies identify E-cad as a selective suppressor of transformation by Gli1 and point to the Sonic Hedgehog–Gli1 pathway as a key regulator of the β-catenin switch in epithelial cells and cancers.

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Abbreviations

Shh:

Sonic Hedgehog

EMT:

epithelial-mesenchymal transition

DN:

dominant-negative

WT:

wild-type

BCC:

basal cell carcinoma

shRNA:

short-hairpin RNA

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Acknowledgements

We thank Eric Fearon and Frank Kolligs for Tcf4ΔN31 cells, and Bert Vogelstein, M Takeichi, Robert Kay and Cara J Gottardi for plasmids. This work was supported by Grants CA094030 and CA065686 from the US National Cancer Institute.

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Authors and Affiliations

  1. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA

    X Li, S M Lobo-Ruppert & J M Ruppert

  2. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    W Deng, S M Lobo-Ruppert & J M Ruppert

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  1. X Li
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  2. W Deng
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  4. J M Ruppert
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Correspondence to J M Ruppert.

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

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Li, X., Deng, W., Lobo-Ruppert, S. et al. Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin. Oncogene 26, 4489–4498 (2007). https://doi.org/10.1038/sj.onc.1210241

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