Regulation of VDR Expression in <i>Apc</i>-Mutant Mice, Human Colon Cancers and Adenomas

Giardina, Charles; Nakanishi, Masayoshi; Khan, Awaad; Kuratnik, Anton; Xu, Wanli; Brenner, Bruce M.; Rosenberg, Daniel W.

doi:10.1158/1940-6207.capr-14-0371

Cited by 20 publications

(21 citation statements)

References 72 publications

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“…Enrichment for binding sites of VDR, which belongs to the Thyroid hormone receptor-related factor (NR1) family, was also detected in the intersection. It has been suggested that vitamin D has no effect on tumor reduction in APC-deficient mice and that VDR expression is lost in the majority of the colon cancer cells (Giardina et al, 2015 ). Interestingly, the analysis also revealed enrichment for binding sites of β-catenin which interacts as a cofactor with members of the TCF-7-related factor family to activate Wnt target gene expression (see Supplementary Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

Computational Identification of Key Regulators in Two Different Colorectal Cancer Cell Lines

et al. 2016

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Transcription factors (TFs) are gene regulatory proteins that are essential for an effective regulation of the transcriptional machinery. Today, it is known that their expression plays an important role in several types of cancer. Computational identification of key players in specific cancer cell lines is still an open challenge in cancer research. In this study, we present a systematic approach which combines colorectal cancer (CRC) cell lines, namely 1638N-T1 and CMT-93, and well-established computational methods in order to compare these cell lines on the level of transcriptional regulation as well as on a pathway level, i.e., the cancer cell-intrinsic pathway repertoire. For this purpose, we firstly applied the Trinity platform to detect signature genes, and then applied analyses of the geneXplain platform to these for detection of upstream transcriptional regulators and their regulatory networks. We created a CRC-specific position weight matrix (PWM) library based on the TRANSFAC database (release 2014.1) to minimize the rate of false predictions in the promoter analyses. Using our proposed workflow, we specifically focused on revealing the similarities and differences in transcriptional regulation between the two CRC cell lines, and report a number of well-known, cancer-associated TFs with significantly enriched binding sites in the promoter regions of the signature genes. We show that, although the signature genes of both cell lines show no overlap, they may still be regulated by common TFs in CRC. Based on our findings, we suggest that canonical Wnt signaling is activated in 1638N-T1, but inhibited in CMT-93 through cross-talks of Wnt signaling with the VDR signaling pathway and/or LXR-related pathways. Furthermore, our findings provide indication of several master regulators being present such as MLK3 and Mapk1 (ERK2) which might be important in cell proliferation, migration, and invasion of 1638N-T1 and CMT-93, respectively. Taken together, we provide new insights into the invasive potential of these cell lines, which can be used for development of effective cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Computational Identification of Key Regulators in Two Different Colorectal Cancer Cell Lines

et al. 2016

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“…For example, others have found that VDR mRNA or protein levels are reduced in human colon tumors (7,28) and other cancers (29–31) . Forty percent of colon tumors have mutations in the K-RAS gene (9) and previous research has shown that RAS activating mutations suppress 1,25(OH) 2 D action in some cells (10–12,32–34) but enhance 1,25(OH) 2 D action in MG-63, HeLa, and COS-1 kidney cells (33,35) .…”

Section: Discussionmentioning

confidence: 99%

“…The proximal promoter region of the VDR gene is hypermethylated in breast cancer cell lines (21) and some adrenocortical carcinomas (40) . In addition, inhibition of DNA methylation using 5′-aza-2′-deoxycytidine increased VDR expression and 1,25(OH) 2 D-mediated growth arrest in breast cancer cell lines (21) and VDR expression in HT-29 colon cancer cells (7) . In contrast, Habano et al (41) reported that inhibition of DNA methylation had no effect on VDR mRNA expression in several colon cancer cell models.…”

Section: Discussionmentioning

confidence: 99%

“…Although there is evidence that 1,25(OH) 2 D action may protect against colon cancer, some studies have shown that VDR levels fall in the early stages of colon cancer (6,7) and that 1,25(OH) 2 D resistance may develop during cancer progression (8) . This suggests that the molecular mutations that develop during colon cancer can regulate cellular events that antagonize signaling through the VDR.…”

Section: Introductionmentioning

confidence: 99%

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Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression

DeSmet

Fleet

2017

The Journal of Steroid Biochemistry and Molecular Biology

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High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer. RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways. We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D (1,25(OH)2D)-mediated gene expression in cultured colon and intestinal cell lines. Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12V) significantly reduced 1,25(OH)2D-induced activity of both a human 25-hydroxyvitamin D, 24 hydroxyase (CYP24A1) promoter-luciferase and an artificial 3X vitamin D response element (VDRE) promoter-luciferase reporter gene. Young Adult Mouse Colon (YAMC) and Rat Intestinal Epithelial (RIE) cell lines with stable expression of mutant H-RAS had suppressed 1,25(OH)2D-mediated induction of CYP24A1 mRNA. The RAS effects were associated with lower Vitamin D receptor (VDR) mRNA and protein levels in YAMC and RIE cells and they could be partially reversed by VDR overexpression. RAS-mediated suppression of VDR levels was not due to either reduced VDR mRNA stability or increased VDR gene methylation. However, chromatin accessibility to the VDR gene at the proximal promoter (−300 bp), an enhancer region at −6 kb, and an enhancer region located in exon 3 was significantly reduced in RAS transformed YAMC cells (YAMC-RAS). These data show that constitutively active RAS signaling suppresses 1,25(OH)2D-mediated gene transcription in colon epithelial cells by reducing VDR gene transcription but the mechanism for this suppression is not yet known. These data suggest that cancers with RAS-activating mutations may be less responsive to vitamin D mediated treatment or chemoprevention.

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“…Although the kidney is the main source of serum 1,25D 3 levels, the extra-renally synthesized 1,25D 3 , which acts locally in an autocrine and paracrine manner, is an indispensable source for the cancer-preventive action of vitamin D. However, during tumor development the expression of the different molecules of the vitamin D system in the affected tissue becomes deregulated. In undifferentiated colorectal adenocarcinomas not only CaSR expression, but also expression of VDR and CYP27B1 is lower than in differentiated tumors (Bareis et al, 2002 ; Bises et al, 2004 ; Giardina et al, 2015 ). Whether these phenomena are linked or not, needs to be determined.…”

Section: Effect Of the Casr On Expression Of The Vitamin D Systemmentioning

confidence: 99%

Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer

Aggarwal

Kállay

2016

Front. Physiol.

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There is epidemiological evidence for the cancer preventive effect of dietary calcium (Ca2+) and vitamin D. This effect is strongest in colorectal cancer (CRC). The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D3), bound to its receptor, the vitamin D receptor (VDR) regulates the expression of hundreds of different genes in a cell- and tissue-specific manner. While Ca2+ acts through multiple mechanisms and pathways, some of its effects are mediated by the calcium-sensing receptor (CaSR). The joint action of Ca2+ and 1,25D3 is due to the fact that both regulate some of the main processes involved in the development of various cancers, such as proliferation, differentiation, apoptosis, migration, and inflammation. Moreover, 1,25D3, bound to VDR can induce translation of the CaSR, while the amount and activity of the CaSR affects 1,25D3 signaling. However, the complexity of the cross-talk between the CaSR and the vitamin D system goes beyond regulating similar pathways and affecting each other's expression. Our aim was to review some of the mechanisms that drive the cross-talk between the vitamin D system and the CaSR with a special focus on the interaction in CRC cells. We evaluated the molecular evidence that supports the epidemiological observation that both vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR.

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Regulation of VDR Expression in Apc-Mutant Mice, Human Colon Cancers and Adenomas

Cited by 20 publications

References 72 publications

Computational Identification of Key Regulators in Two Different Colorectal Cancer Cell Lines

Computational Identification of Key Regulators in Two Different Colorectal Cancer Cell Lines

Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression

Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer

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