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

Abstract

Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell-and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr −/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.V itamin D is obtained naturally from limited dietary sources. It is also generated by cutaneous conversion of 7-dehydrocholesterol in the presence of adequate surface solar UV-B radiation, which varies with latitude and time of year (1). Vitamin D has attracted broad clinical interest because insufficiency or deficiency is widespread in several populations worldwide (2-4). Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. 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 (5-11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12). A large prospective study associated vitamin D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers [head and neck squamous cell carcinoma (HNSCC), esophageal, pancreatic, stomach, and colorectal cancers] and leukemias (13). VDR gene polymorphi...

The Renin–Angiotensin System Mediates EGF Receptor–Vitamin D Receptor Cross-Talk in Colitis-Associated Colon Cancer

“…In agreement with these studies, we found that VDR deletion, which increases EGFR signals, also significantly enhanced nuclear βcatenin in malignant colonocytes, 49.2±11.3% in tumors from Vdr /− vs. 28.8±7.1% in tumors from Vdr +/+ mice (Fig 2C, p<0.05, n=4 adenomas/genotype). Not surprisingly, βcatenin targets, Myc and cyclin D1 (6, 39, 40) were also increased in Vdr −/− tumors (Figs 2A-B) consistent with reports that vitamin D signals suppress Myc and cyclin D1 in colon cancer cells (41, 42). …”

A Humanized Mouse Model of Hereditary 1,25-Dihydroxyvitamin D–Resistant Rickets Without Alopecia

“…There is a clear precedent for this action, because many nuclear receptors including those for the estrogens and androgens exhibit properties such that they are activated through mechanisms independent of their cognate ligands (43)(44)(45)(46)(47). With respect to the VDR, there are numerous hints of this possibility as well, associated directly with the receptor's ability to interact with the specific transcription factor targets of other signaling pathways both on or off DNA (18,19); a recent report that the role of VDR in fat cell differentiation may be dissociated from the influence of 1,25(OH) 2 D 3 [independent of 1,25(OH) 2 D 3 ] may also be relevant and deserving of further exploration (48). Interestingly, a recent analysis of VDR binding sites on a genome-wide scale has revealed that although the vast majority are induced by 1,25(OH) 2 D 3 , relatively robust levels of VDR can be found in the absence of 1,25(OH) 2 D 3 at a rather substantial number of sites on the genome (13,21,22,49).…”

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

“…One possibility is that in vivo VDR binding is modulated by protein-protein interactions with co-factors: SP1 and ETS1 are known to modulate VDR binding, and there is some evidence that interactions between SP1 and VDR may enable modulation of genes that lack a classical VDR recognition motif [43,44]. Several other proteins are known to bind in association with VDR, including NR4A1 and c-MYC [45,46]. CTCF is known to modulate DNA binding via protein-protein interactions with other nuclear receptors [47-49].…”