title: GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells.
abstract: In melanoma cells, high expression of the transcription factor GLI2 is associated with increased invasive potential and loss of E-cadherin expression, an event reminiscent of the epithelial-to-mesenchymal transition (EMT). Herein, we provide evidence that GLI2 represses E-cadherin gene (CDH1) expression in melanoma cells via distinct mechanisms, enhancing transcription of the EMT-activator ZEB1 and cooperative repression of CDH1 gene transcription via direct binding of both GLI2 and ZEB1 to two closely positioned Kruppel-like factor-binding sites within the CDH1 promoter. GLI2 silencing rescued CDH1 expression except in melanoma cell lines in which the CDH1 promoter was hypermethylated. Proximity ligation assays identified GLI2-ZEB1 complexes in melanoma cell nuclei, proportional to endogenous GLI2 and ZEB1 expression, and whose accumulation was enhanced by the classical EMT inducer TGF-β. These data identify GLI2 as a critical modulator of the cadherin switch in melanoma, a molecular process that is critical for metastatic spread of the disease.
authors.affiliation: Institut Curie, Team 'TGF-β and Oncogenesis', Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.
authors.forename: Carole Y
authors.initials: CY
authors.lastname: Perrot
authors.forename: Cristèle
authors.initials: C
authors.lastname: Gilbert
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Antonio
authors.initials: A
authors.lastname: Postigo
authors.forename: Delphine
authors.initials: D
authors.lastname: Javelaud
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
mesh_terms: D015703:Antigens, CD; D001483:Base Sequence; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000075746:Zinc Finger Protein Gli2
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C082593:GLI2 protein, human; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000075746:Zinc Finger Protein Gli2
keywords: E-cadherin; GLI2; ZEB1; gene expression; melanoma