Vitamin D and Wnt/β-catenin Pathway in Colon Cancer: Role and regulation of DICKKOPF genes

Instituto de Investigaciones Biomédica Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, E-28029 Madrid, Spain.
Anticancer research (Impact Factor: 1.83). 09/2008; 28(5A):2613-23.
Source: PubMed


Colorectal cancer is a major health problem worldwide. Aberrant activation of the Wingless-type mouse mammary tumour virus integration site family (Wnt)/beta-catenin signalling pathway due to mutation of adenomatous polyposis coli (APC), beta-catenin (CTNNB1) or AXIN genes is the most common and initial alteration in sporadic colorectal tumours. Numerous epidemiological and experimental studies have indicated a protective action of vitamin D against colorectal cancer. Previous work has demonstrated that the most active vitamin D metabolite, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits beta-catenin transcriptional activity by promoting vitamin D receptor (VDR) binding to beta-catenin and the induction of E-cadherin expression. Recently, 1,25(OH)2D3 has been shown to distinctly regulate two genes encoding the extracellular Wnt inhibitors DICKKOPF-1 and DICKKOPF-4 (DKK-1, DKK-4). By an indirect transcriptional mechanism, 1,25(OH)2D3 increases the expression of DKK-1 RNA and protein, which acts as a tumour suppressor in human colon cancer cells harbouring endogenous mutations in the Wnt/beta-catenin pathway. In contrast, 1,25(OH)2D3 represses DKK-4 transcription by inducing direct VDR binding to its promoter. Unexpectedly, DKK-4 is a target of the Wnt/beta-catenin pathway and is up-regulated in colorectal tumours, and it has been shown to increase cell migration and invasion and to promote a proangiogenic phenotype. Together, these results show that 1,25(OH)2D3 exerts a complex set of regulatory actions leading to the inhibition of the Wnt/beta-catenin pathway in colon cancer cells that is in line with its protective effect against this neoplasia.

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    • "This relationship became even more significant in females in the Newfoundland population, while in the Ontario population the association between vitamin D intake and lower methylation was observed only in early stage tumors, but not in late stage tumors (Rawson et al., 2012). These data confer further insights in the mechanisms regulating the transcriptional activating effect of vitamin D on DKK1 expression described in vitro (Aguilera et al., 2007; Pendas-Franco et al., 2008). "
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    ABSTRACT: Epigenetic mechanisms play a crucial role in regulating gene expression. The main mechanisms involve methylation of DNA and covalent modifications of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of different epigenetic mechanisms is mediated by enzymes acting in the nucleus. Modifications in DNA methylation are performed mainly by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, while a plethora of enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs) regulate covalent histone modifications. In many diseases, such as cancer, the epigenetic regulatory system is often disturbed. Vitamin D interacts with the epigenome on multiple levels. Firstly, critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation. Secondly, VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers, such as HATs, HDACs, HMTs, and with chromatin remodelers. Thirdly, a number of genes encoding for chromatin modifiers and remodelers, such as HDMs of the Jumonji C (JmjC)-domain containing proteins and lysine-specific demethylase (LSD) families are primary targets of VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review we will discuss regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome, and evaluate its impact in health and disease.
    Frontiers in Physiology 04/2014; 5:164. DOI:10.3389/fphys.2014.00164 · 3.53 Impact Factor
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    • "Interestingly, TGF-β treatment decreased levels of TCF-4 transcription factor that interacts with β-catenin to regulate DKK-1 expression [35]. Further, we found a significant reduction of TCF-4 in untreated as well as TGF-β -treated cells lacking β-catenin (Figure 4, E), thus being consistent to the fact that nuclear complex formation of β-catenin/TCF-4 takes place during canonical Wnt-signaling pathway [28], [35]. These data strongly suggest that β-catenin regulates Dkk-1 mRNA expression in IEC in response to TGF-β and is, similar to Dkk-1, involved in the regulation of TGF-β-induced IL-13 expression in IEC. "
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    ABSTRACT: One of the most challenging conditions in Crohn's disease (CD) patients is the treatment of perianal fistulae. We have recently shown that epithelial-to-mesenchymal transition (EMT) plays a crucial role during CD-fistulae development. Dickkopf-homolog 1 (DKK-1) is known to play a key role during EMT. Here, we investigated a role for DKK-1 in the pathogenesis of CD-associated fistulae. Dkk-1 protein expression in CD-fistula specimens were investigated by immunohistochemistry. Colonic lamina propria fibroblasts (CLPF) were obtained from either non-IBD control patients or patients with fistulizing CD. HT-29 intestinal epithelial cells (IEC) were either grown as monolayers or spheroids. Cells were treated with either TNF-α, TGF-β or IL-13. Knock-down of DKK-1 or β-Catenin was induced in HT-29-IEC by siRNA technique. mRNA expression was determined by real-time-PCR. Dkk-1 protein was specifically expressed in transitional cells lining the fistula tracts. TGF-β induced DKK-1 mRNA expression in HT-29-IEC, but decreased it in fistula CLPF. On a functional level, DKK-1 knock-down prevented TGF-β-induced IL-13 mRNA expression in HT-29-IEC. Further, loss of β-Catenin was accompanied by reduced levels of DKK-1 and, again, IL-13 in IEC in response to TGF-β. In turn, treatment of HT-29-IEC as well as fistula CLPF with IL-13 resulted in decreased levels of DKK-1 mRNA. Treatment with TNF-α or the bacterial wall component, muramyl-dipeptide, decreased DKK-1 mRNA levels in HT-29-IEC, but enhanced it in fistula CLPF. We demonstrate that DKK-1 is strongly expressed in cells lining the CD-fistula tracts and regulates factors involved in EMT initiation. These data provide evidence for a role of DKK-1 in the pathogenesis of CD-associated perianal fistulae.
    PLoS ONE 11/2013; 8(11):e78882. DOI:10.1371/journal.pone.0078882 · 3.23 Impact Factor
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    • "The chemopreventive properties of the active metabolite of vitamin D, 1α25(OH)2D3, stem from its ability to inhibit proliferation and angiogenesis, to induce apoptosis and differentiation, and involve its anti-inflammatory properties (Lamprecht and Lipkin, 2003; Lipkin and Lamprecht, 2006). The Wnt/β-catenin signaling oncogenic pathway appears to be an important target of the chemopreventive action of vitamin D3 (Palmer et al., 2001; Pendas-Franco et al., 2008; Shah et al., 2003; Shah et al., 2006). However, a number of cancer cell lines (Kumagai et al., 2003), including colon cancer cell lines tested in our laboratory, display limited response to vitamin D3 in vitro, and VDR expression is downregulated in late stages of colon cancer (Palmer et al., 2004), implying that vitamin D exerts some of its biological activities in a VDR independent manner, or that it targets cells in the tumor microenvironment. "
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    ABSTRACT: Tumor associated macrophages mediate the link between inflammation and cancer progression. Here we showed that macrophage-derived soluble factors induce canonical Wnt signaling in colon cancer cells and promote their growth. Tumor cells induced the release of IL-1β from macrophages, which induced phosphorylation of GSK3β, stabilized β-catenin, enhanced TCF-dependent gene activation, and induced the expression of Wnt target genes in tumor cells. Neutralization experiments using anti IL-1β specific antibodies, or silencing of IL-1β in THP1 macrophages, revealed that IL-1β was required for macrophages to induce Wnt signaling and to support the growth of tumor cells. Constitutive activation of STAT1 in THP1 macrophages was essential for the induction of IL-1β and thus for the activation of β–catenin signaling in tumor cells. Vitamin D3, an effective chemopreventive agent, interrupted this crosstalk by blocking the constitutive activation of STAT1 and the production of IL-1β in macrophages, and therefore- in a vitamin D receptor dependent manner- inhibited the ability of macrophages to activate Wnt signaling in colon carcinoma cells. Our data therefore established that vitamin D3 exerts its chemopreventive activity by interrupting a cross-talk between tumor epithelial cells and the tumor microenvironment.
    Oncogene 09/2009; 28(44):3892-902. DOI:10.1038/onc.2009.247 · 8.46 Impact Factor
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