Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin

Oncogene. 2007 Jul 5;26(31):4489-98. doi: 10.1038/sj.onc.1210241. Epub 2007 Feb 5.


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 beta-catenin at the cell membrane. Loss of E-cad during developmental epithelial-mesenchymal transitions can switch beta-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 beta-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 beta-catenin. Inhibition of Wnt-beta-catenin signaling by dominant negative Tcf4 selectively blocked in vitro transformation by Gli1. In Gli1-transgenic mice, infiltrating skin tumor cells expressed active, unphosphorylated beta-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 beta-catenin switch in epithelial cells and cancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cadherins / metabolism*
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / pharmacology
  • Epithelial Cells
  • Kidney
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Transgenic
  • Rats
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factor 4
  • Transcription Factors / metabolism*
  • Transcription Factors / pharmacology
  • Wnt Proteins / metabolism
  • Zinc Finger Protein GLI1
  • beta Catenin / metabolism*


  • Cadherins
  • DNA-Binding Proteins
  • Gli1 protein, rat
  • Kruppel-Like Transcription Factors
  • Snai2 protein, rat
  • Snail Family Transcription Factors
  • Tcf4 protein, rat
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • Zinc Finger Protein GLI1
  • beta Catenin