Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of
vitamin D3 (D3) in the skin which supplies >90% of the body's requirement.
Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (
CYP27B1) to produce
1,25(OH)2D3, or through the action of
CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by
CYP27B1, CYP27A1, and
CYP24A1. The active forms of D3, in addition to regulating
calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-
melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the
vitamin D receptor (VDR) and/or as most recently demonstrated through action on
retinoic acid orphan receptors (ROR)α and RORγ. With respect to
melanoma, low levels of 25(
OH)D are associated with thicker
tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the
vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or
CYP27B1 in
melanoma with
tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for
CYP24A1 (inactivating 24-hydroxylase), indicating that this
enzyme, while inactivating
1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by
CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and
melanoma progression and disease outcome. Therefore, we propose that defects in
vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect
melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of
melanoma should be taken into consideration when applying
vitamin D management for
melanoma therapy.