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 #
5P01CA090890-08
Application #
8288257
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
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$1,650,953
Indirect Cost
$458,891
Name
Oregon State University
Department
None
Type
Organized Research Units
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Beaver, Laura M; Buchanan, Alex; Sokolowski, Elizabeth I et al. (2014) Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention. Mol Nutr Food Res 58:2001-13
Wong, Carmen P; Hsu, Anna; Buchanan, Alex et al. (2014) Effects of sulforaphane and 3,3'-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS One 9:e86787
Kang, Y; Nian, H; Rajendran, P et al. (2014) HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell Death Dis 5:e1476
W Watson, Gregory; M Beaver, Laura; E Williams, David et al. (2013) Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention. AAPS J 15:951-61
Benninghoff, Abby D; Williams, David E (2013) The role of estrogen receptor ? in transplacental cancer prevention by indole-3-carbinol. Cancer Prev Res (Phila) 6:339-48
Wang, Rong; Lohr, Christiane V; Fischer, Kay et al. (2013) Epigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer. Int J Cancer 132:1004-12
Rajendran, Praveen; Kidane, Ariam I; Yu, Tian-Wei et al. (2013) HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics 8:612-23
Shorey, Lyndsey E; Madeen, Erin P; Atwell, Lauren L et al. (2013) Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: maternal diets rich in indole-3-carbinol versus sulforaphane. Toxicol Appl Pharmacol 270:60-9
Kaur, Pushpinder; Shorey, Lyndsey E; Ho, Emily et al. (2013) The epigenome as a potential mediator of cancer and disease prevention in prenatal development. Nutr Rev 71:441-57
Shorey, Lyndsey E; Castro, David J; Baird, William M et al. (2012) Transplacental carcinogenesis with dibenzo[def,p]chrysene (DBC): timing of maternal exposures determines target tissue response in offspring. Cancer Lett 317:49-55

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