The NIH Roadmap stipulates that epigenetics is a research priority. Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable, and dietary factors have been shown to "de-repress" epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. The overall long-term objectives of this P01 are to better understand the mechanisms by which beneficial epigenetic changes can be brought about by dietary agents, to identify and characterize epigenetic biomarkers that can be applied in the clinical setting, and to evaluate those biomarkers in preclinical and translational studies. With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the cell cycle and apoptosis. E. Ho will investigate "Chemoprevention of prostate cancer, HDAC inhibition, and DNA methylation" (Project 1), D.E. Williams will study "Transplacental chemoprevention of lung tumors and lymphomas" (Project 2), and R.H. Dashwood will examine "Chemoprevention of colon cancer, HDAC inhibition, and histone status" (Project 3). The overall significance of the work is that it seeks to provide new epigenetic insights into the prevention and treatment of colon, prostate, and lung cancer, as well as lymphoma, which are listed consistently among the top causes of cancer-related deaths in the US. This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA090890-10
Application #
8732423
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Program Officer
Malone, Winfred F
Project Start
2001-04-01
Project End
2015-04-30
Budget Start
2014-08-18
Budget End
2015-04-30
Support Year
10
Fiscal Year
2014
Total Cost
$1,392,370
Indirect Cost
$210,962
Name
Texas A&M University
Department
Type
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
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

Showing the most recent 10 out of 111 publications