Vitamin D and skin cancer: A problem in gene regulation

The skin is the major source of Vitamin D3 (cholecalciferol), and ultraviolet light (UV) is critical for its formation. Keratinocytes, the major cell in the epidermis, can further convert Vitamin D3 to its hormonal form, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol). 1,25(OH)2D3 in turn stimulates the differentiation of keratinocytes, raising the hope that 1,25(OH)2D3 may prevent the development of malignancies in these cells. Skin cancers (squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanomas) are the most common cancers afflicting humans. UV exposure is linked to the incidence of these cancers-UV is thus good and bad for epidermal health. Our focus is on the mechanisms by which 1,25(OH)2D3 regulates the differentiation of keratinocytes, and how this regulation breaks down in transformed cells. Skin cancers produce 1,25(OH)2D3, contain ample amounts of the Vitamin D receptor (VDR), and respond to 1,25(OH)2D3 with respect to induction of the 24-hydroxylase, but fail to differentiate in response to 1,25(OH)2D3. Why not? The explanation may lie in the overexpression of the DRIP complex, which by interfering with the normal transition from DRIP to SRC as coactivators of the VDR during differentiation, block the induction of genes required for 1,25(OH)2D3-induced differentiation.