Project 3 studies food components as histone deacetylase (HDAC) inhibitors. HDAC inhibitors 'de-repress'epigenetically silenced genes, such as P21/WAF1, through Sp1/Sp3 transcription factor binding sites in the corresponding gene promoters, causing growth arrest/apoptosis in cancer cells. The PI has championed the view that dietary HDAC inhibitors might act similarly in the therapeutic setting, but because of their ingestion in foods they also serve a chemopreventive role via epigenetic 'priming'of gene expression in normal cells. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (I3C), and the cruciferous vegetables from which they derive, are effective chemopreventive agents in the colon because, in addition to their blocking activities during the initiation phase, they inhibit HDAC activity and alter the pattern of histone modifications (acetylation, methylation, phosphorylation) in cancer cells, thereby de-repressing epigenetically silenced genes such as P21 that regulate the cell cycle and apoptosis.
Aims 1 -3 start with mechanistic studies in human colon cancer cells, followed by preclinical dose-response experiments in a rat colon cancer model, ending with human translational work (colonoscopy screening).
Aim 1. In human colon cancer cells treated with SFN and I3C, define the changes HDACs, histone status (acetylation/methylation/phosphorylation), and Sp1/Sp3 transcription factor binding on the promoter region of P21, and mechanisms of HDAC inhibition. Study the DNA methylation status of the P21 promoter and changes in non-histone targets such as p53.
This aim uses immunoblotting, ChlP/re-ChIP, co-IP and qRT-PCR to examine reversible histone modifications, p21 de-repression, and HDAC inhibition/turnover.
Aim 2. In the 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) rat colon carcinogenesis model, examine chemoprevention of colon cancer using whole foods (broccoli sprouts, Brussels sprouts) and individual phytochemicals (SFN, I3C), Validate epigenetic biomarkers from Aim 1 as predictors of colon tumor outcome. Integrate with Projects 1 and 2 by examining other tissues (lung, thymus, prostate) for epigenetic biomarkers that might be applied in the clinical setting, such as during colonoscopy screening.
Aim 3. In patients presenting for screening colonoscopy, recruit low, mid, and high cruciferous vegetable consumers and assess tissue biopsy specimens and circulating blood cells for HDAC activity and histone status. Measure SFN metabolites as a biomarker of cruciferous vegetable intake, using LC/MS/MS in the Epigenetic/Translational Biomarkers core, and the mutation status of K-ras in colon biopsies.

Public Health Relevance

In addition to genetic changes affecting DNA sequence information, we now realize that cancer development involves so-called epigenetic events, which represent a major new research priority area at NIH. One aspect of intense current interest concerns the histone (protein) modifications that silence tumor suppressor genes in cancer cells. We find that dietary agents can reverse such modifications, thereby re-expressing tumor suppressor genes and triggering cancer cells to arrest their growth and/or commit suicide via apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA090890-08
Application #
8376153
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$362,676
Indirect Cost
Name
Oregon State University
Department
Type
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Johnson, Gavin S; Li, Jia; Beaver, Laura M et al. (2016) A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a co-activator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res :
Wang, Rong; Kang, Yuki; Löhr, Christiane V et al. (2016) Reciprocal regulation of BMF and BIRC5 (Survivin) linked to Eomes overexpression in colorectal cancer. Cancer Lett 381:341-8
Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng et al. (2016) HDAC6 activity is not required for basal autophagic flux in metastatic prostate cancer cells. Exp Biol Med (Maywood) 241:1177-85
Abbas, Ata; Hall, J Adam; Patterson 3rd, William L et al. (2016) Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines. Biochem Cell Biol 94:71-81
Ertem, Furkan; Dashwood, Wan-Mohaiza; Rajendran, Praveen et al. (2016) Development of a murine colonoscopic polypectomy model (with videos). Gastrointest Endosc 83:1272-6
Zhang, Zhenzhen; Atwell, Lauren L; Farris, Paige E et al. (2016) Associations between cruciferous vegetable intake and selected biomarkers among women scheduled for breast biopsies. Public Health Nutr 19:1288-95
Kim, Hyemee; Banerjee, Nivedita; Ivanov, Ivan et al. (2016) Comparison of anti-inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis. Mol Nutr Food Res 60:1912-23
Kim, Eunah; Bisson, William H; Löhr, Christiane V et al. (2016) Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors. Curr Top Med Chem 16:714-31
Harper Jr, Tod A; Morré, Jeff; Lauer, Fredine T et al. (2015) Analysis of dibenzo[def,p]chrysene-deoxyadenosine adducts in wild-type and cytochrome P450 1b1 knockout mice using stable-isotope dilution UHPLC-MS/MS. Mutat Res Genet Toxicol Environ Mutagen 782:51-6
Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng et al. (2015) Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells. Mol Nutr Food Res 59:1954-61

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