Abstract
We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by β-catenin, including the stem cell marker keratin 15, contain vitamin D response elements (VDREs) and several are induced independently of TCF/Lef. The VDR is required for β-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergises with β-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear β-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high β-catenin and low VDR levels. In mice, EB1089 prevents β-catenin induced trichofolliculomas, while in the absence of VDR β-catenin induces tumours resembling BCCs. We conclude that VDR is a TCF/Lef-independent transcriptional effector of the Wnt pathway and that vitamin D analogues have therapeutic potential in tumors with inappropriate activation of Wnt signalling.
Highlights
Adult mammalian epidermis is maintained by stem cells that selfrenew and produce progeny that differentiate along the lineages of the hair follicle (HF), sebaceous gland (SG) and interfollicular epidermis (IFE) [1,2]
To investigate whether or not nuclear b-catenin and vitamin D receptor (VDR) expression correlated with tumour type in human skin tumours, we examined a panel of 59 human tumours, which were categorised as basal cell carcinomas or having elements of HF differentiation (trichofolliculomas (TF), trichoepithelioma (TE), or sebaceous TF (STF) (Table S4)
In wild type skin the combined activation of Wnt and VDR by their endogenous ligands is required for normal anagen
Summary
Adult mammalian epidermis is maintained by stem cells that selfrenew and produce progeny that differentiate along the lineages of the hair follicle (HF), sebaceous gland (SG) and interfollicular epidermis (IFE) [1,2]. One group, represented by PADI3, Gli and Tubb, was induced by EB1089 alone or in combination with Wnt3A, in wild type and DNLef cells but not in VDR null cells (Figure 2A) We conclude that these genes are VDR dependent, TCF/Lef independent Wnt targets. In keeping with the more extensive ectopic HF morphogenesis in D2 than D4 transgenics, ectopic follicles in D2 mice that were heterozygous for the VDR contained cells expressing many transcriptional target genes of b-catenin/VDR complexes that are HF lineage markers, including K15, PADI3, S1003A, K31, K35, K71, K34, Gli, and Dlx (Figure 4J, M, O, Q, S, U, W, Y, A’). We conclude that low levels of VDR correlate with infiltrative BCCs (p,0.001)
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