Butyrate and vitamin D 3 induce transcriptional attenuation at the cyclin D1 locus in colonic carcinoma cells
ABSTRACT In stimulating maturation of colonic carcinoma cells, the short chain fatty acid butyrate, and 1alpha,25-dihydroxyvitamin D(3), were shown to attenuate transcription of the cyclin D1 gene, giving rise to truncated transcripts of this locus. Moreover, a sequence which is highly conserved in the human, mouse, rat, and dog genome was found in the 4 kb long intron 3 of the human cyclin D1 gene, and is capable of forming a hairpin structure similar to that of microRNA precursors. The expression of this sequence is also decreased by the attenuation. Thus, the transcriptional attenuation at the cyclin D1 locus not only down-regulates the expression of this key gene in mucosal cell maturation and tumorigenesis, but may also abrogate the generation of a molecule that encompasses this conserved sequence in cyclin D1 intron 3.
SourceAvailable from: Gregory A Plotnikoff[Show abstract] [Hide abstract]
ABSTRACT: Interdisciplinary scientific evaluation of the human microbiota has identified three enteric microbial biotransformations of particular relevance for human health and well-being, especially cancer. Two biotransformations are counterproductive; one is productive. First, selective bacteria can reverse beneficial hepatic hydroxylation to produce toxic secondary bile acids, especially deoxycholic acid. Second, numerous bacterial species can reverse hepatic detoxification-in a sense, retoxify hormones and xeonobiotics-by deglucuronidation. Third, numerous enteric bacteria can effect a very positive biotransformation through the production of butyrate, a small chain fatty acid with anti-cancer activity. Each biotransformation is addressed in sequence for its relevance in representative gastrointestinal and extra-intestinal cancers. This is not a complete review of their connection with every type of cancer. The intent is to introduce the reader to clinically relevant microbial biochemistry plus the emerging evidence that links these to both carcinogenesis and treatment. Included is the evidence base to guide counseling for potentially helpful dietary adjustments.05/2014; 3(3):33-43. DOI:10.7453/gahmj.2014.021
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ABSTRACT: Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.Nature Reviews Cancer 04/2014; DOI:10.1038/nrc3691 · 29.54 Impact Factor
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ABSTRACT: Purpose: We previously showed that epidermal growth factor receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D (VD) suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. VD inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. Experimental Design: To examine VDR-RAS interactions, we treated Vdr+/+ and Vdr-/- mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Westerns, immunostaining and real time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr+/+ mice. EGFR regulation of VDR was examined in hypomorphic Egfr ((Wa2)) and Egfr(wildtype) mice. Ang II-induced EGFR activation was studied in cell culture. Results: Vdr deletion significantly increased tumorigenesis, activated EGFR and β catenin signaling and increased colonic RAS components: including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared to tumors from Egfr(Waved2) mice, tumors from Egfr(wildtype) mice showed up-regulated Snail1, a suppressor of VDR, and down-regulated VDR. Conclusions: VDR suppresses the colonic RAS cascade, limits EGFR signals and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and down-regulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.Clinical Cancer Research 09/2014; DOI:10.1158/1078-0432.CCR-14-0209 · 8.19 Impact Factor