Transcriptional Profiling of Keratinocytes Reveals a Vitamin D-Regulated Epidermal Differentiation Network

1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] regulates mineral homeostasis and exhibits potent anti-proliferative, prodifferentiative, and immunomodulatory activities. It mediates these effects by binding to the vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. As a result of keratinocyte differentiation and anti-proliferation activities, 1,25(OH)2D3 and its synthetic analogs are therapeutically effective in psoriasis and show promise for the treatment of actinic keratosis and squamous cell carcinoma. To elucidate the VDR signaling pathway in keratinocytes, we examined the gene expression profile with 1,25(OH)2D3 treatment using oligonucleotide microarrays. Out of the 12,600 genes investigated, 82 were upregulated and 16 were downregulated and many of these were involved in differentiation, proliferation, and immune response. We have identified three vitamin D-responsive chromosomal loci (1p36, 19q13, and 6p25) and show the induction of various class II tumor suppressor/growth-regulatory genes in response to 1,25(OH)2D3. Finally, quantitative differences in gene expression revealed a vitamin D-regulated differentiation network and identified peptidylarginine deiminases, kallikreins, serine proteinase inhibitor family members, Kruppel-like factor 4, and c-fos as vitamin D-responsive genes, whose protein products may play an important role in epidermal differentiation in normal and diseased state.