title: GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells.
abstract: We recently identified GLI2, the most active of GLI transcription factors, as a direct TGF-β/SMAD target, whose expression in melanoma cells is associated with increased invasiveness and metastatic capacity. In this work, we provide evidence that high GLI2 expression is inversely correlated with that of the melanocyte-specific transcription factor M-microphthalmia transcription factor (M-MITF) and associated transcriptional program. GLI2-expressing cell lines were characterized by the loss of M-MITF-dependent melanocytic differentiation markers and reduced pigmentation. The balance between M-MITF and GLI2 expression did not correlate with the presence or absence of BRAF-activating mutations, but rather was controlled by two distinct pathways: the TGF-β pathway, which favors GLI2 expression, and the protein kinase A (PKA)/cAMP pathway, which pushes the balance toward high M-MITF expression. Furthermore, overexpression and knockdown experiments demonstrated that GLI2 and M-MITF reciprocally repress each other's expression and control melanoma cell invasion in an opposite manner. These findings thus identify GLI2 as a critical transcription factor antagonizing M-MITF function to promote melanoma cell phenotypic plasticity and invasive behavior.
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Javelaud
authors.forename: Vasileia-Ismini
authors.initials: VI
authors.lastname: Alexaki
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Pierrat
authors.forename: Keith S
authors.initials: KS
authors.lastname: Hoek
authors.forename: Sylviane
authors.initials: S
authors.lastname: Dennler
authors.forename: Leon
authors.initials: L
authors.lastname: Van Kempen
authors.forename: Corine
authors.initials: C
authors.lastname: Bertolotto
authors.forename: Robert
authors.initials: R
authors.lastname: Ballotti
authors.forename: Simon
authors.initials: S
authors.lastname: Saule
authors.forename: Véronique
authors.initials: V
authors.lastname: Delmas
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010858:Pigmentation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D051785:Smad Proteins / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D051739:Microphthalmia-Associated Transcription Factor; D009687:Nuclear Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000075746:Zinc Finger Protein Gli2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases