title: Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas.
abstract: The transcription factor interferon regulatory factor 6 (IRF6) regulates craniofacial development and epidermal proliferation. We recently showed that IRF6 is a component of a regulatory feedback loop that controls the proliferative potential of epidermal cells. IRF6 is transcriptionally activated by p63 and induces its proteasome-mediated down-regulation, thereby limiting keratinocyte proliferative potential. We hypothesized that IRF6 may also be involved in skin carcinogenesis. Hence, we analyzed IRF6 expression in a large series of squamous cell carcinomas (SCCs) and found a strong down-regulation of IRF6 that correlated with tumor invasive and differentiation status. IRF6 down-regulation in SCC cell lines and primary tumors correlates with methylation on a CpG dinucleotide island located in its promoter region. To identify the molecular mechanisms regulating IRF6 potential tumor suppressive activity, we performed a genome-wide analysis by combining ChIP sequencing for IRF6 binding sites and gene expression profiling in primary human keratinocytes after siRNA-mediated IRF6 depletion. We observed dysregulation of cell cycle-related genes and genes involved in differentiation, cell adhesion, and cell-cell contact. Many of these genes were direct IRF6 targets. We also performed in vitro invasion assays showing that IRF6 down-regulation promotes invasive behavior and that reintroduction of IRF6 into SCC cells strongly inhibits cell growth. These results indicate a function for IRF6 in suppression of tumorigenesis in stratified epithelia.
authors.affiliation: Department of Dermatology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Botti
authors.forename: Giulia
authors.initials: G
authors.lastname: Spallone
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Barbara
authors.initials: B
authors.lastname: Marinari
authors.forename: Valentina
authors.initials: V
authors.lastname: Pinetti
authors.forename: Sergio
authors.initials: S
authors.lastname: Galanti
authors.forename: Paolo D'Onorio
authors.initials: PD
authors.lastname: De Meo
authors.forename: Francesca
authors.initials: F
authors.lastname: De Nicola
authors.forename: Federica
authors.initials: F
authors.lastname: Ganci
authors.forename: Tiziana
authors.initials: T
authors.lastname: Castrignanò
authors.forename: Graziano
authors.initials: G
authors.lastname: Pesole
authors.forename: Sergio
authors.initials: S
authors.lastname: Chimenti
authors.forename: Luisa
authors.initials: L
authors.lastname: Guerrini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fanciulli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002468:Cell Physiological Phenomena / Q000235:genetics; D049109:Cell Proliferation; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D015603:Keratinocytes / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D012878:Skin Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D025521:Tumor Suppressor Proteins