GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells.
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.
['Perrot|Carole Y|CY|', 'Gilbert|Cristèle|C|', 'Marsaud|Véronique|V|', 'Postigo|Antonio|A|', 'Javelaud|Delphine|D|', 'Mauviel|Alain|A|']
D015703:Antigens, CD D001483:Base Sequence D001665:Binding Sites D015820:Cadherins D045744:Cell Line, Tumor D002467:Cell Nucleus D019175:DNA Methylation D015972:Gene Expression Regulation, Neoplastic D055785:Gene Knockdown Techniques D020868:Gene Silencing D018398:Homeodomain Proteins D006801:Humans D051741:Kruppel-Like Transcription Factors D008545:Melanoma D008954:Models, Biological D008969:Molecular Sequence Data D009687:Nuclear Proteins D011401:Promoter Regions, Genetic D011485:Protein Binding D012097:Repressor Proteins D012878:Skin Neoplasms D000071250:Snail Family Transcription Factors D014157:Transcription Factors D014158:Transcription, Genetic D016212:Transforming Growth Factor beta D000071799:Zinc Finger E-box-Binding Homeobox 1 D000075746:Zinc Finger Protein Gli2
GLI2 ZEB1 melanoma E-cadherin gene expression