Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer

Abstract

The VDR acting with or without its principal ligand 1,25(OH)2D regulates two central processes in the skin, interfollicular epidermal (IFE) differentiation and hair follicle cycling (HFC). Calcium is an important co-regulator with 1,25(OH)2D at least of epidermal differentiation. Knockout of the calcium sensing receptor (CaSR) in addition to VDR accelerates the development of skin cancer in mice on a low calcium diet. Coactivators such as mediator 1 (aka DRIP205) and steroid receptor coactivator 3 (SRC3) regulate VDR function at different stages of the differentiation process, with Med 1 essential for hair follicle differentiation and early stages of epidermal differentiation and proliferation and SRC3 essential for the latter stages of differentiation including formation of the permeability barrier and innate immunity. The corepressor of VDR, hairless (HR), is essential for hair follicle cycling, although its effect on epidermal differentiation in vivo is minimal. In its regulation of HFC and IFE VDR controls two pathways-wnt/β-catenin and sonic hedgehog (SHH). In the absence of VDR these pathways are overexpressed leading to tumor formation. Whereas, VDR binding to β-catenin may block its activation of TCF/LEF1 sites, β-catenin binding to VDR may enhance its activation of VDREs. 1,25(OH)2D promotes but may not be required for these interactions. Suppression of SHH expression by VDR, on the other hand, requires 1,25(OH)2D. The major point of emphasis is that the role of VDR in the skin involves a number of novel mechanisms, both 1,25(OH)2D dependent and independent, that when disrupted interfere with IFE differentiation and HFC, predisposing to cancer formation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Keywords: Calcium sensing receptor; Cancer; Coregulators; Epidermal differentiation; Hair follicle cycling; Vitamin D receptor.

Figure 1. The E-cadherin/catenin complex

Both calcium and 1,25(OH)₂D induce formation of the E-cadherin complex. Major components include E-cadherin itself spanning the membrane and forming intercellular contacts through a calcium link, a number of catenins including β-catenin and p120, and enzymes involved with PIP phosphorylation to PIP3. PIP3 activates other enzymes involved in the differentiation process including PLC-γ1, Akt, and PDK1. PLC-γ hydrolyzes PIP2 to IP3 and DAG, which promote differentiation by increasing calcium release from intracellular stores and activating PKC, respectively. Figure modified from model originally published by Xie et al. Molec Biol Cell 20:1695–1704.

Figure 2. Coactivators of VDR function

The major coactivator complexes regulating VDR function in the keratinocyte are Mediator (aka DRIP) and SRC. The Mediator complex is most highly expressed in basal keratinocytes where it regulates proliferation and hair differentiation. The SRC complexes are most highly expressed in the more differentiated layers of the epidermis where they regulate barrier formation and innate immunity. Both complexes are involved in more intermediate stages of differentiation.

Figure 3. Oncogenic lncRNA expression in VDR null keratinocytes

H19 and Hottip, lncRNAs overexpressed in a number of tumors are over expressed in the epidermis and keratinocytes of VDR null mice. Data taken from Jiang and Bikle, Exper Dermatol 23:147–150

Figure 4. SCC formed spontaneously in a mouse lacking both VDR and CaSR

These tumors begin to appear about 6mo of age when the mice are placed on a low calcium diet.