IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes

• Published in: The EMBO journal Vol. 30; no. 22; pp. 4571 - 4585
• Main Authors: Restivo, Gaetana, Nguyen, Bach-Cuc, Dziunycz, Piotr, Ristorcelli, Elodie, Ryan, Russell J H, Özuysal, Özden Yalçin, Di Piazza, Matteo, Radtke, Freddy, Dixon, Michael J, Hofbauer, Günther F L, Lefort, Karine, Dotto, G Paolo
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 16.11.2011; Nature Publishing Group UK; Springer Nature B.V; Nature Publishing Group
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Cycle Proteins - metabolism; Cell Differentiation; Cell Proliferation; Cellular biology; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - physiology; DNA-Binding Proteins - metabolism; EMBO24; EMBO37; ErbB Receptors - biosynthesis; ErbB Receptors - genetics; Genes, Tumor Suppressor; Homeodomain Proteins - metabolism; Humans; Interferon; Interferon Regulatory Factors - biosynthesis; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; keratinocytes; Keratinocytes - cytology; Keratinocytes - metabolism; Keratinocytes - physiology; Mice; Mice, Inbred NOD; Mice, SCID; Molecular biology; Notch; Oncogene Protein p21(ras) - metabolism; p63; Promoter Regions, Genetic; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; squamous cell carcinoma; Transcription Factor HES-1; Tumors; tumour suppression; tumour suppression; keratinocytes; p63; Notch; squamous cell carcinoma
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1038/emboj.2011.325

While the pro‐differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch‐dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte‐derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation‐related genes, while it is not required for induction of ‘canonical’ Notch targets like p21 WAF1/Cip1 , Hes1 and Hey1. Down‐modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo , promoting ras‐induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression. Using molecular and genetic approaches, this study identifies the interferon regulatory factor 6 (IRF6) as an essential and direct mediator of Notch/CSL pro‐differentiation and tumour suppressive functions in keratinocytes.