Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas

Elisabetta Botti, Giulia Spallone, Francesca Moretti, Barbara Marinari, Valentina Pinetti, Sergio Galanti, Paolo D Onorio De Meo, Francesca De Nicola, Federica Ganci, Tiziana Castrignanò, Graziano Pesole, Sergio Chimenti, Luisa Guerrini, Maurizio Fanciulli, Giovanni Blandino, Michael Karin, Antonio Costanzo

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13710-13715
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number33
DOIs
Publication statusPublished - Aug 16 2011

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Interferon Regulatory Factors
Squamous Cell Carcinoma
Neoplasms
Down-Regulation
Keratinocytes
Carcinogenesis
cdc Genes
CpG Islands
Gene Expression Profiling
Proteasome Endopeptidase Complex

Keywords

  • HRas
  • Oncogene-induced senescence
  • Ovo-like 1(drosophila)
  • Skin cancer
  • Transforming growth factor-β

ASJC Scopus subject areas

  • General

Cite this

Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas. / Botti, Elisabetta; Spallone, Giulia; Moretti, Francesca; Marinari, Barbara; Pinetti, Valentina; Galanti, Sergio; De Meo, Paolo D Onorio; De Nicola, Francesca; Ganci, Federica; Castrignanò, Tiziana; Pesole, Graziano; Chimenti, Sergio; Guerrini, Luisa; Fanciulli, Maurizio; Blandino, Giovanni; Karin, Michael; Costanzo, Antonio.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 33, 16.08.2011, p. 13710-13715.

Research output: Contribution to journalArticle

Botti, E, Spallone, G, Moretti, F, Marinari, B, Pinetti, V, Galanti, S, De Meo, PDO, De Nicola, F, Ganci, F, Castrignanò, T, Pesole, G, Chimenti, S, Guerrini, L, Fanciulli, M, Blandino, G, Karin, M & Costanzo, A 2011, 'Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 33, pp. 13710-13715. https://doi.org/10.1073/pnas.1110931108
Botti, Elisabetta ; Spallone, Giulia ; Moretti, Francesca ; Marinari, Barbara ; Pinetti, Valentina ; Galanti, Sergio ; De Meo, Paolo D Onorio ; De Nicola, Francesca ; Ganci, Federica ; Castrignanò, Tiziana ; Pesole, Graziano ; Chimenti, Sergio ; Guerrini, Luisa ; Fanciulli, Maurizio ; Blandino, Giovanni ; Karin, Michael ; Costanzo, Antonio. / Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 33. pp. 13710-13715.
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AU - Pinetti, Valentina

AU - Galanti, Sergio

AU - De Meo, Paolo D Onorio

AU - De Nicola, Francesca

AU - Ganci, Federica

AU - Castrignanò, Tiziana

AU - Pesole, Graziano

AU - Chimenti, Sergio

AU - Guerrini, Luisa

AU - Fanciulli, Maurizio

AU - Blandino, Giovanni

AU - Karin, Michael

AU - Costanzo, Antonio

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N2 - 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.

AB - 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.

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