Vitamin D and cancer: a review of molecular mechanisms

Abstract

The population-based association between low vitamin D status and increased cancer risk can be inconsistent, but it is now generally accepted. These relationships link low serum 25OHD (25-hydroxyvitamin D) levels to cancer, whereas cell-based studies show that the metabolite 1,25(OH)2D (1,25-dihydroxyvitamin D) is a biologically active metabolite that works through vitamin D receptor to regulate gene transcription. In the present review we discuss the literature relevant to the molecular events that may account for the beneficial impact of vitamin D on cancer prevention or treatment. These data show that although vitamin D-induced growth arrest and apoptosis of tumour cells or their non-neoplastic progenitors are plausible mechanisms, other chemoprotective mechanisms are also worthy of consideration. These alternative mechanisms include enhancing DNA repair, antioxidant protection and immunomodulation. In addition, other cell targets, such as the stromal cells, endothelial cells and cells of the immune system, may be regulated by 1,25(OH)2D and contribute to vitamin D-mediated cancer prevention.

Figure 1

Summary of vitamin D mediated gene transcription through the vitamin D receptor (VDR). (A) Schematic showing alternative models for binding of VDR-RXR dimers to DNA and the regulation of gene transcription by vitamin D. In model A, RXR (yellow hexagon) is resident. VDR (green rectangle) binds after being activated by ligand, releasing any co-repressor complexes if they are present. In model B, VDR and RXR dimerize then bind to DNA. Both model A and B lead to the recruitment of additional co-activators, e.g. p300/CBP (star) and SRC-1 (orange oval) for histone acetylation, ATP-dependent chromatin remodeling factors like SWI/SNF, the mediator complex (dark purple rectangle) for recruitment and activation of RNA polymerase II (light blue oval). Model C shows that the vitamin D-VDR complex can also recruit co-repressor complexes with histone deacetylase activity (purple oval) and DNA methyl transferase activity (green circle) to gene promoters. This will suppress gene transcription. (B) Schematic showing the distribution of VDR binding sites in the genome of osteoblasts [211] and lymphoblastoid cells [38] relative to the transcription start site (TSS) of a gene. Values are given as a percentage of total VDR binding sites and were determined by chromatin immunoprecipitation coupled to DNA arrays (ChIP-chip) or next-generation sequencing (ChIP-seq).

Figure 2

A summary of the negative effects of cancer on vitamin D metabolism and action.

Figure 3

A summary of the potential molecular events regulated by 1,25(OH)₂ D (VD) relevant to cancer.