Vitamin D receptor, a tumor suppressor in skin.

Vitamin D and calcium are well-established regulators of keratinocyte proliferation and differentiation. Therefore, it was not a great surprise that deletion of the vitamin D receptor (VDR) should predispose the skin to tumor formation, and that the combination of deleting both the VDR and calcium sensing receptor (CaSR) should be especially pro-oncogenic. In this review I have examined 4 mechanisms that appear to underlie the means by which VDR acts as a tumor suppressor in skin. First, DNA damage repair is curtailed in the absence of the VDR, allowing mutations in DNA to accumulate. Second and third involve the increased activation of the hedgehog and β-catenin pathways in the epidermis in the absence of the VDR, leading to poorly regulated proliferation with reduced differentiation. Finally, VDR deletion leads to a shift in the expression of long noncoding RNAs toward a more oncogenic profile. How these different mechanisms interact and their relative importance in the predisposition of the VDR null epidermis to tumor formation remain under active investigation.