The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis

• Published in: PloS one 2008-01, Vol.3 (1), p.e1483-e1483
• Main Authors: Pálmer, Héctor G, Anjos-Afonso, Fernando, Carmeliet, Geert, Takeda, Hikaru, Watt, Fiona M
• Format: Article
• Language: English
• Subjects: Animals; Baldness; Basal cell carcinoma; beta Catenin - physiology; Binding sites; Biochemistry/Transcription and Translation; Carcinoma; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Cell Biology/Morphogenesis and Cell Biology; Cell Differentiation - physiology; Cell growth; Colorectal cancer; Cysts; Dermatology/Hair and Nail Diseases; Dermatology/Skin Cancers, including Melanoma and Lymphoma; Developmental Biology/Cell Differentiation; Developmental Biology/Morphogenesis and Cell Biology; Developmental Biology/Stem Cells; Differentiation; Epidermis; Epidermis - metabolism; Epidermis - pathology; Gene expression; Genes; Genomes; Growth factors; Hair; Keratin; Keratinocytes - metabolism; LEF protein; Ligands; Medical research; Mice; Mice, Knockout; Molecular biology; Molecular Biology/Transcription Initiation and Activation; Mutation; Oncology/Skin Cancers; Promoter Regions, Genetic; Proteins; Receptors, Calcitriol - physiology; Regulatory sequences; Rodents; Signal Transduction; Signaling; Skin cancer; Skin Neoplasms - physiopathology; Stem cells; Transcription; Transcription factors; Trends; Tumors; Vitamin D; Vitamin D receptors; Wnt protein; Wnt Proteins - metabolism; Wnt Proteins - physiology; β-Catenin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001483

We have investigated how Wnt and vitamin D receptor signals regulate epidermal differentiation. Many epidermal genes induced by beta-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 beta-catenin induced hair follicle formation in adult epidermis, and the vitamin D analog EB1089 synergizes with beta-catenin to stimulate hair differentiation. Human trichofolliculomas (hair follicle tumours) are characterized by high nuclear beta-catenin and VDR, whereas infiltrative basal cell carcinomas (BCCs) have high beta-catenin and low VDR levels. In mice, EB1089 prevents beta-catenin induced trichofolliculomas, while in the absence of VDR beta-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.