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.
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.
|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; LÃ¶hr, 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 modelÂ (withÂ 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; LÃ¶hr, 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; MorrÃ©, 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