Dietary histone deactylase inhibitors in prostate cancer prevention

描述(申请人提供)：前列腺癌是最常见的非皮肤癌，也是美国男性癌症死亡的第二大原因。启动和促进前列腺癌进展的确切病因尚不清楚，但表观遗传改变和饮食/生活方式因素已成为重要的促成因素。在前列腺癌期间，乙酰化模式的改变和组蛋白脱乙酰酶的增加是明显的。使用抑制HDACs的药理学药物来预防和治疗癌症已经引起了人们的极大兴趣。HDAC抑制剂导致乙酰化组蛋白增加，选择性地诱导癌细胞细胞周期停滞和凋亡，并已在癌症临床试验中显示出希望。萝卜硫素(SFN)是十字花科蔬菜中发现的一种化合物，在动物模型中可抑制肿瘤生长，并能抑制前列腺中的HDAC活性。基于这些发现，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，导致组蛋白乙酰化和p21和bax等基因的下调，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降低前列腺癌风险的机制。这些研究的目的是确定新的前列腺癌化学保护剂，这些药物通过抑制和下调HDAC基因表达而起作用，从而预防癌症。具体地说，我们建议1)表征饮食中SFN对前列腺癌形成小鼠前列腺癌发生的影响。工作假设是SFN治疗将抑制TRAMP小鼠前列腺癌的发展。抑制肿瘤的发展将与抑制HDAC活性、增加乙酰化组蛋白水平和促进细胞凋亡有关。2)研究HDAC抑制对SFN诱导的细胞凋亡和化学预防的要求。工作假设是，SFN抑制HDAC是导致SFN诱导p21和Bax表达和细胞凋亡的关键机制。3)在人类中检测饮食消费对SFN代谢、HDAC活性和乙酰化组蛋白状态的影响。工作假设是，前列腺癌高危男性的高十字花科蔬菜摄入量将与外周血中HDAC活性降低和前列腺组织中乙酰化组蛋白水平增加有关。

DESCRIPTION (provided by applicant): 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. The working 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.