Cross talk of aryl-hydrocarbon-receptor (ahr) - and vitamin d receptor (vdr) - signaling in human keratinocytes

BACKGROUND/AIM:Vitamin D receptor (VDR), activated upon binding of 1,25(OH)2D3, was described as a tumor suppressor in the skin. New biological functions of non-classical vitamin D derivatives were recently identified, that are mediated via binding to alternate receptors, including the aryl hydrocarbon receptor (AHR) and that indicate functional interaction between AHR and VDR signaling in various human tissues. We aimed to gain further insights into the cross-talk of VDR and AHR signaling in skin photo-carcinogenesis. MATERIALS AND METHODS:Using real-time quantitative PCR, we analyzed in vitro effects of the complete carcinogen UVB and of 1,25(OH)2D3 on the expression of members of the AHR and VDR pathways in human keratinocytes revealing characteristics of different stages of skin photo-carcinogenesis. RESULTS:In precancerous HaCaT keratinocytes, induction of a target gene of AHR-mediated transcription (CYP1A1) was markedly stronger after treatment with UVB, as compared to treatment with 1,25(OH)2D3. In contrast, in SCL-1 cells (that reveal the complete phenotype of malignant transformation), expression of CYP1A1 was higher after treatment with 1,25(OH)2D3 as compared to treatment with UVB. The classical VDR target CYP24A1 was up-regulated by 1,25(OH)2D3, but not by UVB, in both cell lines. However, the combined treatment with UVB strongly enhanced the 1,25(OH)2D3-mediated up-regulation of CYP24A1 exclusively in SCL-1, but not in HaCaT cells. CONCLUSION:There is a differential regulation of VDR and AHR target genes by UVB and 1,25(OH)2D3 in HaCaT and SCL-1 cells, that points to a complex and highly orchestrated network of vitamin D derivatives (and other photoproducts) and its relevance for photo-carcinogenesis.