Chemoprevention of Prostate Cancer, HDAC Inhibition, and DNA Methylation

前列腺癌是最常见的非皮肤癌症，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/生活方式因素已被认为是重要的因素。在前列腺癌中，通过表观遗传模式的改变，如组蛋白去乙酰化和启动子甲基化，基因沉默是显而易见的。用于癌症预防和治疗的组蛋白去乙酰化酶（HDAC）或DNA甲基转移酶（DNMT）抑制剂的药理作用引起了人们的极大兴趣，并在癌症临床试验中显示出前景。我们报道了十字花科蔬菜中发现的一种化合物萝卜硫素（SFN）在动物模型中抑制肿瘤生长并抑制前列腺中HDAC活性。体外研究表明，异硫氰酸酯抑制前列腺癌细胞启动子甲基化和HDAC活性。基于这些发现，我们提出了以下中心假设：在前列腺中，硫素作为HDAC和DNMT1抑制剂，导致组蛋白和蛋白质乙酰化和启动子去甲基化增强，诱导细胞周期阻滞/凋亡，从而预防癌症。这些研究的目的是确定植物化学物质通过表观遗传修饰改变基因表达的机制，从而预防前列腺癌的发展。具体来说，Aim 1验证了SFN和吲哚-3-甲醇（130）靶向表观遗传改变导致前列腺癌增殖减少的假设。目的2研究富含SFN和ISC的饮食对体内前列腺表观遗传标志物和癌症的影响。工作假设是，这些化合物将抑制前列腺肿瘤的发展，改变HDAC活性和靶向异常DNA甲基化模式，导致控制细胞凋亡和细胞增殖的基因去抑制。在Aim 3的翻译研究中，使用随机、双盲、安慰剂对照试验来验证西兰花芽补充剂会增加前列腺中SFN代谢物，抑制HDAC活性，并导致启动子去甲基化，从而增加前列腺中组蛋白/非组蛋白乙酰化和启动子去甲基化的假设。这一建议的独特之处在于，我们将在细胞、动物和有前列腺癌风险的患者中通过饮食干预试验来检验中心假设和相关机制。

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.