Dietary histone deactylase inhibitors in prostate cancer prevention

前列腺癌是最常见的非皮肤癌，也是第二大致癌原因。 美国男性死于癌症。启动和促进疾病进展的确切病因 前列腺癌仍然未知，但表观遗传改变和饮食/生活方式因素已经出现 重要的促成因素。在前列腺癌期间，乙酰化模式的改变和 组蛋白脱乙酰酶很明显。抑制HDAC治疗癌症的药理药物的使用 预防和治疗已引起人们的极大关注。HDAC抑制剂导致乙酰化水平增加 组蛋白选择性地诱导癌细胞的细胞周期停滞和凋亡，并在癌症中显示出希望 临床试验。我们最近报道了十字花科植物中发现的萝卜硫素(SFN) 蔬菜，在动物模型中抑制肿瘤生长，并抑制前列腺中的HDAC活性。基于 在这些发现中，我们提出了以下中心假设： 萝卜硫素在前列腺中作为HDAC的抑制剂，导致组蛋白的诱导 乙酰化和去抑制基因，如p21和bax，有助于细胞周期停滞和 细胞凋亡，从而预防癌症。 这些研究的长期目标是确定十字花科蔬菜的作用机制。 降低前列腺癌风险。这些研究的目的是确定新的前列腺化学保护措施。 通过抑制和降低HDAC基因表达来预防癌症的药物。 具体地说，我们建议1)表征饮食中SFN对前列腺癌发生的影响 一种用于前列腺癌发生的小鼠。工作假设是SFN治疗将抑制前列腺 肿瘤在流浪鼠体内的发展。抑制肿瘤的发展将与抑制 HDAC活性，乙酰化组蛋白水平升高，促进细胞凋亡。2)检查 HDAC抑制对SFN诱导的细胞凋亡和化学预防的要求。工作假说是 SFN对HDAC的抑制是SFN诱导p21和Bax表达的关键机制。 3)研究人类饮食中食用十字花科蔬菜对SFN的影响 代谢、HDAC活性和乙酰化组蛋白状态。工作假说是高等十字花科 蔬菜摄入量将与外周血液中HDAC活性降低和乙酰化程度增加有关 前列腺癌高危人群前列腺组织中组蛋白水平的研究

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.