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)2 D 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 Med1 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.

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

“…77 Genomic activities of vitamin D are initiated when the VDR-ligand complex forms a heterodimer with the retinoid receptor, RXR, in the cytoplasm which then translocates to the nucleus, where it binds to vitamin D responsive elements in target genes and recruits either coactivators or corepressors to regulate transcription. 71,72,78 The VDR is expressed in all organs and almost all cells of the body, where it regulates a variety of their functions in addition to the regulation of calcium metabolism. 70,71,73 Approximately 3% of the mammalian genome is regulated, directly and/or indirectly by signaling secondary to activation of the VDR.…”

Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

“…Its effects are mediated via the vitamin D receptor (VDR), which after agonist activation and dimer formation with RXR binds to the VDR responsive element (VDRE) to influence expression of responsive genes [14, 17–19]. …”

Non-classical effects of vitamin D

“…В кератиноцитах экспрессируется VDR [14], а также синтезируется 1,25(ОН) 2 D за счет экспрессии как 25-, так и 1α-гидроксилазы [15]. В регуляции процессов, обеспечивающих функционирование эпидермиса, уча-ствуют сигнальные пути, активирующиеся при действии кальция на рецепторы-сенсоры кальция и при связыва-нии 1,25(ОН) 2 D с VDR кератиноцитов.…”

“…В пролиферирующих кератиноци-тах VDR взаимодействует с комплексом DRIP/Mediator. При дефиците VDR и его наиболее известного коакти-ватора DRIP 205, а также Med1 и Med21 наблюдается повышение пролиферации кератиноцитов, снижение апоптоза и неправильный набор маркеров дифференци-ровки [15]. На поверхности кератиноцитов также имеется рецептор-сенсор кальция, который участвует в контроле процесса дифференцировки кератиноцитов за счет име-ющегося в эпидермисе градиента кальция [16].…”

“…В исследованиях на животных моделях был показан эффект VDR по предотвращению рака кожи, вызванно-го как УФ-излучением, так и химическими веществами; при нарушении сигнального пути рецептора-сенсора кальция и дефекте VDR наблюдался спонтанный процесс образования опухолей [15]. Однако, клинических данных недостаточно для разработки рекомендаций по допол-нительной терапии.…”