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Ultraviolet Irradiation Represses PATCHED Gene Transcription in Human Epidermal Keratinocytes through an Activator Protein-1-Dependent Process

¹ Laboratory of Genetic Instability and Cancer, Centre National de la Recherche Scientifique UPR2169, Institut Gustave Roussy, Villejuif Cedex, France; ² L’OREAL, Life Sciences Advanced Research, Centre C. Zviak, Clichy, France; ³ Department of Biosciences, Karolinska Institutet, Huddinge, Sweden; and ⁴ INSERM U532, Hôpital Saint Louis, Paris, France

Basal cell carcinoma (BCC) is one of the major types of skin cancer arising from keratinocytes. The SONIC HEDGEHOG pathway is deregulated in 100% of sporadic BCCs, as indicated by the overexpression of PATCHED, whose product encodes the receptor of SONIC HEDGEHOG, in 100% of analyzed BCCs. Reverse transcription-PCR analysis revealed that exposure to UVB irradiation, which is a risk factor known to contribute to BCC development, induces a strong and sharp decrease of PATCHED mRNA level both in vitro and ex vivo. Transcription of a reporter gene driven by the 4.4-kb 5'-regulatory region of the human PATCHED gene was shown to be down-regulated after UVB irradiation. Furthermore, overexpression of c-JUN, a member of the activator protein (AP)-1 family, induced repression of the PATCHED promoter. The role of AP-1 in UVB-induced PATCHED repression was confirmed in mouse embryonic fibroblasts knocked out for c-JUN NH₂-terminal protein kinase. This study thus provides the first evidence of UV-induced down-regulation at the transcriptional level of the BCC-associated tumor suppressor PATCHED relying on activation of the AP-1 oncogenic pathway.