Prostate cancer is the most frequently diagnosed non-cutaneous cancer, and is the second leading cause of cancer death in American men. The precise etiologic factors that initiate and enhance the progression of prostate cancer remains unknown, but epigenetic alterations and diet/lifestyle factors have come forth as significant contributing factors. During prostate cancer, alterations in acetylation patterns and increases in histone deacetylases are apparent. The use of pharmacological agents that inhibit HDACs for cancer prevention and therapy have gained significant interest. HDAC inhibitors cause increases in acetylated histones, selectively induce cell cycle arrest and apoptosis in cancer cells and have shown promise in cancer clinical trials. We have recently reported that sulforaphane (SFN), a compound found in cruciferous vegetables, suppresses tumor growth in animal models and inhibits HDAC activity in prostate. Based on these findings we formulated the following central hypothesis: Sulforaphane acts as an inhibitor of HDAC in the prostate, resulting in the induction of histone acetylation and de-repression of genes such as p21 and Bax, contributing to cell cycle arrest and apoptosis, and thus cancer prevention. The long term goal of these studies is to determine the mechanisms by which cruciferous vegetables act to decrease prostate cancer risk. The objective of these studies is to identify novel prostate chemoprotective agents that act via HDAC inhibition and de-repression of gene expression leading to cancer prevention. Specifically, we propose to 1) Characterize the effects of dietary SFN on development of prostate cancer in a mouse for prostate carcinogenesis. The working hypothesis is that SFN treatment will suppress prostate tumor development in TRAMP mice. Suppression of tumor development will be associated with inhibition of HDAC activity, increases in the levels of acetylated histones and enhancement of apoptosis. 2) Examine the requirement of HDAC inhibition for SFN induced apoptosis and chemoprevention. The working hypothesis is that HDAC inhibition by SFN is a key mechanism leading to SFN-induced p21 and Bax expression and apoptosis.3) Examine in humans the effects dietary consumption of cruciferous vegetables on SFN metabolism, HDAC activity and acetylated histone status. The working hypothesis is that high cruciferous vegetable intake will be associated with lower HDAC activity in peripheral blood and increase acetylated histone levels in prostate tissue of men at high risk for prostate cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122906-02
Application #
7413331
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2007-05-01
Project End
2012-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
2
Fiscal Year
2008
Total Cost
$335,954
Indirect Cost
Name
Oregon State University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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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
Atwell, Lauren L; Beaver, Laura M; Shannon, Jackilen et al. (2015) Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention. Curr Pharmacol Rep 1:102-111
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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
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
Meyer, Megan; Bauer, Rebecca N; Letang, Blanche D et al. (2014) Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers. Am J Physiol Lung Cell Mol Physiol 306:L269-76
Meyer, Megan; Kesic, Matthew J; Clarke, John et al. (2013) Sulforaphane induces SLPI secretion in the nasal mucosa. Respir Med 107:472-5
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
Li, Yanyan; Zhang, Tao; Li, Xiaoqin et al. (2013) Kinetics of sulforaphane in mice after consumption of sulforaphane-enriched broccoli sprout preparation. Mol Nutr Food Res 57:2128-36

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