title: GLI2 Is a Regulator of β-Catenin and Is Associated with Loss of E-Cadherin, Cell Invasiveness, and Long-Term Epidermal Regeneration.
abstract: Uncontrolled hedgehog (HH)/glioma-associated oncogene (GLI) and WNT/β-catenin signaling are important events in the genesis of many cancers including skin cancer and are often implicated in tumor progression, invasion, and metastasis. However, because of 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/glioma-associated oncogene family zinc finger 2 (GLI2)-WNT/β-catenin signaling crosstalk in human keratinocytes. Overexpression 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, matrix metalloproteinase 2, and integrin β1; and increased cell invasion in 3D organotypic cultures. Invasion was reduced by WNT inhibition, thus unveiling the direct role of GLI2/WNT crosstalk in cell invasion. We show that GLI2 overexpression supported long-term epidermal regeneration in 3D organotypic cultures, and resulted in the manifestation of an undifferentiated basal/stem cell-associated phenotype in human keratinocytes. Both these observations are consistent 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 tumorigenesis.
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pantazi
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Emilios
authors.initials: E
authors.lastname: Gemenetzidis
authors.affiliation: Department of Diagnostic and Oral Sciences, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Sreekanth Vootukuri
authors.initials: SV
authors.lastname: Reddy
authors.affiliation: Imaging and Flow Cytometry Core facilities, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Warnes
authors.affiliation: Pathology Core facilities, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Evagora
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trigiante
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Electronic address: m.p.philpott@qmul.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Philpott
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D018613:Microscopy, Confocal; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D015820:Cadherins; D004273:DNA, Neoplasm; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2; D051176:beta Catenin