| Autor: |
Botti, Elisabetta, Spallone, Giulia, Moretti, Francesca, Marinari, Barbara, Pinetti, Valentina, Galanti, Sergio, D'Onorio De Meo, Paolo, De Nicola, Francesca, Ganci, Federica, Castrignanô, Tiziana, Pesole, Graziano, Chimenti, Sergio, Guerrini, Luisa, Fanciulli, Maurizio, Blandin, Giovanni, Karin, Michael, Costanzo, Antonio |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 8/16/2011, Vol. 108 Issue 33, p13710-13715, 6p |
| Abstrakt: |
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 5CC cells strongly inhibits cell growth. These results indicate a function for IRF6 in suppression of tumorigenesis in stratified epithelia. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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