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.

Crosstalk Between Vitamin D and p53 Signaling in Cancer: An Update.

It has now been convincingly shown that vitamin D and p53 signaling protect against spontaneous or carcinogen-induced malignant transformation of cells. The vitamin D receptor (VDR) and the p53/p63/p73 proteins (the p53 family hereafter) exert their effects as receptors/sensors that turn into transcriptional regulators upon stimulus. While the p53 clan, mostly in the nucleoplasm, responds to a large and still growing number of alterations in cellular homeostasis commonly referred to as stress, the nuclear VDR is transcriptionally activated after binding its naturally occurring biologically active ligand 1,25-dihydroxyvitamin D with high affinity. Interestingly, a crosstalk between vitamin D and p53 signaling has been demonstrated that occurs at different levels, has genome-wide implications, and is of high importance for many malignancies, including non-melanoma skin cancer. These interactions include the ability of p53 to upregulate skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Increased pigmentation protects the skin against UV-induced DNA damage and skin photocarcinogenesis, but also inhibits cutaneous synthesis of vitamin D. A second level of interaction is characterized by binding of VDR and p53 protein, an observation that may be of relevance for the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and its family members have been implicated in the direct regulation of the VDR. This review gives an update on some of the implications of the crosstalk between vitamin D and p53 signaling for carcinogenesis in the skin and other tissues, focusing on a genome-wide perspective.

How do estrogens control lymphoma?

In this issue of Blood, Yakimchuk and colleagues show that estrogen receptor ß (ERß) signaling can act tumor-suppressive predominantly through the regulation of genes by ERß in the tumor, not in the microenvironment, and point out new therapeutic strategies.