The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.
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.
Pálmer
Héctor G
HG
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
Anjos-Afonso
Fernando
F
Carmeliet
Geert
G
Takeda
Hikaru
H
Watt
Fiona M
FM
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000502:physiology*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000503:physiopathology*; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
D018167:Receptors, Calcitriol; D051153:Wnt Proteins; D051176:beta Catenin