The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control

Abstract

Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1alpha,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1alpha,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1alpha,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1alpha,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.

Graphical abstract

Fig. 1

Chemistry of 1α,25-(OH)₂ D₃. 1α,25-(OH)₂ D₃ is derived from the 4 cyclopentanoperhydro-phenanthrene ring structure (A, B, C, and D rings) for steroids. In 1α,25-(OH)₂ D₃, the 9,10 carbon–carbon bond of ring B is broken between ring A and rings C and D (arrow, a) and the molecule is technically classified as a seco-steroid. The molecule may then rotate along the bond between ring A and rings C and D (arrow), to provide the structure of 1α,25-(OH)₂ D₃ (a). Stepwise modification of the molecule, involving location of a oxygen atom at position 23 on the C and D ring side chain or removal of the terminal –OH group can have important biological effects (b).

Fig. 2

Schematic representation of the vitamin D receptor (VDR) domain structure. (a) VDR protein backbone and 1α,25-(OH)₂ D₃ ligand-binding pocket. The VDR protein backbone is represented by a ribbon. A space-filling representation of 1α,25-(OH)₂ D₃ is shown within the VDR ligand-binding pocket by an atom-based structure. Conformational modification of the vitamin D side chain may influence ligand binding and transcriptional activity . (b) The human VDR gene domain structure. The human VDR gene is composed of 9 exons that encode domains (A–F). Upon 1α,25(OH)₂ D₃ binding to the hormone ligand-binding domain, VDR is stabilized by the phosphorylation of serine 51 in the DNA-binding domain and serine 208 in the hinge region. VDR associates with the retinoic acid receptor (RXR) through the dimerization domains in E/F. The 1α,25-(OH)₂ D₃–VDR–RXR complex binds to the vitamin D response elements (VDREs) through the DNA-binding domain in the promoters of target genes. Conformational change in VDR results in co-repressor dissociation and enables interaction of the AF2 transactivation domain with stimulatory coactivators, such as steroid receptor coactivators (SRCs), vitamin D receptor-interacting proteins complex and nuclear coactivators.

Fig. 3

Transcriptional regulation by vitamin D. Classical action of 1α,25-(OH)₂ D₃ is mediated by binding of the VDR/RXR complex at VDREs. (a) Transcriptional activation involves the co-activator molecules SRCs, NCoA62, HATs, CBP p300 and other molecules to derepress chromatin. (b) Binding of DRIP to the AF2 domain attracts a complex containing transcription factor 2B (TF2B) and RNA polymerase II (RNA Pol II) for transcription initiation. The presence of the multiprotein complex facilitates increased gene transcription. (c) 1α,25(OH)₂ D₃-mediated transcriptional repression involves VDR–RXR heterodimer association with VDR-interacting repressor (VDIR) bound to E-box-type negative VDREs (nVDREs), dissociation of the HAT co-activator and recruitment of histone deacetylase (HDAC) co-repressor. Williams syndrome transcription factor (WSTF) potentiates transrepression by interacting with a multifunctional, ATP-dependent chromatin-remodelling complex (WINAC) and chromatin. This leads to the repression of genes, such as CYP27B1 (which encodes 1α-OHase) and PTH (which encodes parathyroid hormone). (d) Non-genomic, rapid actions of 1α,25-(OH)₂ D₃ are though activation of mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase (ERK) 1 and 2 cascade through the phosphorylation (P) and activation of Raf by protein kinase C (PKC), partly through induced changes of intra-cellular Ca²⁺ concentration (reproduced from Deeb et al. with kind permission of Dr CS Johnston Roswell Park CI, New York and the publisher).