Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair

Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown if this loss increases ultraviolet-induced (UV) carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte-specific Smad4 deletion (K14.Smad4(−/−)) and wildtype (WT) littermates were chronically UV-irradiated. Compared to WT, K14.Smad4(−/−) mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross-complementation group1 (Ercc1) mRNA was significantly reduced in UV treated K14.Smad4(−/−) skin compared to WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4(−/−) keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4(−/−) keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses (AK). Collectively, Smad4 loss associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus we identified a role for Snail in UV-induced DNA repair.