Stimulation of Sirt1-Regulated FoxO Protein Function by the Ligand-Bound Vitamin D Receptor

Abstract

Vitamin D is obtained from limited dietary sources and UVB-stimulated photoconversion of 7-dehydrocholesterol in skin (36). Hepatic hydroxylation catalyzed by CYP27A1, CYP2R1, and possibly other enzymes generates the major circulating metabolite 25-hydroxyvitamin D (25D). 25D is a relatively long-lived metabolite and is a marker of vitamin D status. 25D is 1␣ hydroxylated in kidney and peripheral tissues to produce hormonal 1,25-dihydroxyvitamin D (1,25D). While renal 1␣ hydroxylation generates much of the circulating 1,25D, extrarenal 1␣ hydroxylation is a critical source of 1,25D in situ in a number of tissues (61). Moreover, while renal CYP27B1 expression/activity is regulated by calcium homeostatic signals (e.g., parathyroid hormone), extrarenal 1␣ hydroxylation is regulated by distinct physiological inputs.1,25D binds the nuclear vitamin D receptor (VDR), which heterodimerizes with related retinoid X receptors (RXRs) to recognize vitamin D response elements (VDREs) in target genes (36). Although initially identified as a regulator of calcium homeostasis, 1,25D is now known to have a broad spectrum of actions. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell cycle arrest and nonmalignant and malignant cell differentiation (14,24,27,34,35,37,46,49). Moreover, epidemiological data provide associations between lack of UVB exposure, vitamin D insufficiency, and the prevalence of certain cancers (16). Notably, a large prospective study associated 25D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers (head and neck squamous cell carcinoma [HNSCC] and esophageal, pancreatic, stomach, and colorectal cancers) and leukemias (23). VDR gene polymorphisms also correlate with protection against different malignancies, including HNSCC (16, 39). The above is noteworthy, as numerous studies have shown that vitamin D insufficiency or deficiency is widespread in temperate populations (26,61).FoxO1, FoxO3a, FoxO4, and FoxO6 transcription factors regulate cell proliferation, differentiation, and metabolism and control longevity (1,10,21,25,52). Serial ablation in mice of genes encoding FoxO proteins revealed that these proteins are bona fide tumor suppressors (7,17,28). FoxO function is inhibited by mitogen-activated PI3 kinase, which stimulates Akt-dependent phosphorylation, nuclear export (1, 10, 25), and proteasomal degradation (17,28). FoxOs are also regulated by acetylation, which can be reversed by the NAD-dependent sirtuin 1 (Sirt1) class III lysine deacetylase (15,30). Acetylation reduces DNA binding and enhances phosphorylation and inactivation (43). Notably, FoxO and c-MYC target genes partially overlap, and FoxO factors repress a subset of c-MYC-induced genes, including CCND2, which encodes cyclin D2 (18,52).We have been interested in understanding the mechanisms regulating the anticancer properties of vitamin D, in particular the molecular genetic events underlying its control of cell proliferation. We noted that there ...

Vitamin D receptor as a master regulator of the c-MYC/MXD1 network

“…We have been using human SCC25 HNSCC cells as a model to investigate mechanisms of 1,25D-induced cell-cycle arrest (19,39). c-MYC overexpression has been implicated in the development of HNSCC (40), and inducible overexpression of c-MYC induces actinic keratosis, a squamous cell cancer precursor (31).…”

“…Potential cancer preventive actions of 1,25D signaling through the VDR can be explained in part by the direct interaction of the VDR with FoxO transcription factors, leading to 1,25D-stimulated FoxO DNA-binding and target gene regulation (19). FoxO proteins regulate cell proliferation, differentiation, and metabolism and control longevity (20)(21)(22)(23).…”

Vitamin D and cancer: a review of molecular mechanisms

“…The function of several FoxO family members is inhibited by MAPK-mediated phosphorylation. Recently An et al [66] showed that 1,25(OH) 2 D treatment regulates binding of FoxO3a and FoxO4 to DNA regulatory regions by stimulating a direct interaction between VDR, FoxO3a or FoxO4, and the FoxO regulators Sirt1 (a class III histone deacetylase) and protein phosphatase 1. Sirt1 and protein phosphatase 1 promote nuclear retention of FoxO proteins by counteracting MAPK-mediated phosphorylation.…”

Vitamin D metabolism and signaling in the immune system

“…VDR/RXR heterodimers can displace DNA-bound nuclear factor of activated T cells (NF-AT), thus repressing cytokine gene expression [32]. We recently, found that the ligand-bound VDR repressed transcription of the gene encoding cyclin D2 via its interaction with FoxO transcription factors [33].…”