GLI2 is a novel regulator of β-catenin and is associated with loss of E-cadherin, cell invasiveness and long-term epidermal regeneration
Journal of Investigative Dermatology
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Uncontrolled HH/GLI and WNT/β-catenin signaling are important events in the genesis of many cancers including skin cancer and are often implicated in tumour progression, invasion and metastasis. However, due to the complexity and context-dependency of both pathways, little is known about HH and WNT interactions in human carcinogenesis. In the current study we provide evidence of HH/GLI2-WNT/β-catenin signaling crosstalk in human keratinocytes. Over-expression of GLI2ΔN in human keratinocytes resulted in cytoplasmic accumulation and nuclear relocalization of β-catenin in vitro and in 3D-organotypic cultures, accompanied by upregulation of WNT genes. Induction of GLI2ΔN, enhanced the β-catenin-dependent transcriptional activation and the subsequent activation of β-catenin target genes including Cyclin-D1. Additionally, GLI2 overexpression was associated with decreased E-cadherin protein levels, increased expression of SNAIL, MMP2 and integrin β1, and with increased cell invasion in 3D-organotypic cultures. Invasion was reduced by Wnt inhibition, thus unveiling direct role of GLI2/Wnt crosstalk in cell invasion. We also showed that GLI2 supported long-term epidermal regeneration in 3D-organotypic cultures and to induce an undifferentiated basal/stem cell-associated phenotype, in line with the role of β-catenin and SNAIL in epidermal stem cell maintenance. This work suggests that GLI2 is a regulator of β-catenin and provides insights into its role in tumourigenesis.