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, silencing of genes via alterations in epigenetic patterns such as histone deacetylation and promoter methylation are apparent. Pharmacological agents that are histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors for cancer prevention and therapy have gained significant interest and have shown promise in cancer clinical trials. We reported that sulforaphane (SFN), a compound found in cruciferous vegetables, suppresses tumor growth in animal models and inhibits HDAC activity in prostate. Studies in vitro showed that isothiocyanates inhibit both promoter methylation and HDAC activity in prostate cancer cells. Based on these findings we formulated the following CENTRAL HYPOTHESIS: Sulforaphane acts as an HDAC and DNMT1 inhibitor in the prostate, causing enhanced histone &protein acetylation and promoter demethylation, and induction of cell cycle arrest/apoptosis, leading to cancer prevention. The objective of these studies is to identify mechanisms by which phytochemicals alter gene expression via epigenetic modifications, and thereby prevent prostate cancer development. Specifically, Aim 1 tests the hypothesis that SFN and indole-3-carbinol (130) that target epigenetic alterations lead to a decrease in prostate cancer proliferation.
Aim 2 investigates the effects of diets rich in SFN and ISC on epigenetic markers and cancer in the prostate in vivo. The working hypothesis is that these compounds will suppress prostate tumor development and will alter HDAC activity and target aberrant DNA methylation patterns leading to de-repression of genes controlling apoptosis and cell proliferation. For translational studies in Aim 3, use a randomized, double-blind, placebo-controlled trial to test the hypothesis that broccoli sprout supplementation will increase SFN metabolites in the prostate, inhibit HDAC activity, and cause promoter demethylation leading to an increase in histone/non-histone protein acetylation and promoter de-methylation in the prostate. The proposal is unique in that we will test the central hypothesis and associated mechanisms in cells, animals, and through a dietary intervention trial in patients at risk for prostate cancer.

Public Health Relevance

The research proposed in this application is significant because strategies that target epigenetic pathways have the potential to dramatically reduce the incidence of prostate cancer, reduce health care costs associated with prostate cancer, and improve the quality of life of thousands of American men. These studies are significant because of the potential to change recommendations for prostate cancer patients and increase their survival through simple dietary choices incorporating easily accessible foods to their diets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
7P01CA090890-10
Application #
8732424
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
2014-08-18
Project End
2015-04-30
Budget Start
2013-09-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2014
Total Cost
$782,490
Indirect Cost
$423,184
Name
Texas A&M University
Department
Type
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Madeen, Erin P; Williams, David E (2017) Environmental PAH exposure and male idiopathic infertility: a review on early life exposures and adult diagnosis. Rev Environ Health 32:73-81
Beaver, Laura M; Kuintzle, Rachael; Buchanan, Alex et al. (2017) Long noncoding RNAs and sulforaphane: a target for chemoprevention and suppression of prostate cancer. J Nutr Biochem 42:72-83
Palomera-Sanchez, Zoraya; Watson, Gregory W; Wong, Carmen P et al. (2017) The phytochemical 3,3'-diindolylmethane decreases expression of AR-controlled DNA damage repair genes through repressive chromatin modifications and is associated with DNA damage in prostate cancer cells. J Nutr Biochem 47:113-119
Chen, Ying-Shiuan; Wang, Rong; Dashwood, Wan-Mohaiza et al. (2017) A miRNA signature for an environmental heterocyclic amine defined by a multi-organ carcinogenicity bioassay in the rat. Arch Toxicol 91:3415-3425
Wang, Rong; Chen, Ying-Shiuan; Dashwood, Wan-Mohaiza et al. (2017) Divergent roles of p120-catenin isoforms linked to altered cell viability, proliferation, and invasiveness in carcinogen-induced rat skin tumors. Mol Carcinog 56:1733-1742
Madeen, Erin P; Löhr, Christiane V; You, Hannah et al. (2017) Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type, Cyp1b1 knockout, and CYP1B1 humanized mice. Mol Carcinog 56:163-171
Johnson, Gavin S; Li, Jia; Beaver, Laura M et al. (2017) A functional pseudogene, NMRAL2P, is regulated by Nrf2 and serves as a coactivator of NQO1 in sulforaphane-treated colon cancer cells. Mol Nutr Food Res 61:
Ertem, Furkan U; Zhang, Wenqian; Chang, Kyle et al. (2017) Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam. Int J Cancer 140:460-468
Kim, Hyemee; Banerjee, Nivedita; Barnes, Ryan C et al. (2017) Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo. Mol Carcinog 56:197-207
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

Showing the most recent 10 out of 121 publications