Chemoprevention of Prostate Cancer, HDAC Inhibition, and DNA Methylation

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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.