Dietary histone deactylase inhibitors in prostate cancer prevention

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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, 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. Theworking 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.