Epigenetic mechanisms of indole-3-carbinol/diindolylemthane and triterpenoids in prevention of prostate inflammation and related disease

过度和慢性炎症可导致许多急性和慢性炎症。 慢性疾病，包括自身免疫性疾病、神经系统疾病、心血管疾病和癌症。增加 有证据表明，慢性炎症与表观遗传改变密切相关， DNA和组蛋白修饰，驱动许多炎症基因表达的变化，如 IL 1R1、IL-1 β、toll样受体2、15-LOX、考克斯-2、CXCL 14、CCL 25、CXCL 6、IL 13、IL 17 C和IL 4 R。重要的 包括吲哚-3-甲醇和三萜类化合物在内的几类天然CAM产物具有生物活性， 和表观遗传修饰特性。我们的初步研究表明：（1）表观遗传的CpG 与野生型相比，TRAMP前列腺肿瘤中炎性基因的甲基化状态发生改变 对照使用MeDIP-seq技术;（2）在2-氨基-1-甲基-6-苯基咪唑并[4，5-B]吡啶（PhIP）诱导的 炎症/高级PIN（HGP），炎症标志物，如 8-oxo-dG、硝基酪氨酸、考克斯-2、p-AKT和PTEN表达增加;（3）炎症浸润增加 在小鼠前列腺特异性Pten-/-HGP中;和（4）吲哚-3-甲醇（I3C）/3，3 ′-二吲哚基甲烷（DIM）， 十字花科蔬菜和来自药用植物、水果和蔬菜的三萜类熊果酸（UA）， 蓝莓，蔓越莓，甜菜和蘑菇，它们在不同的组织中具有有效的抗炎活性， 类型的细胞，被发现触发表观遗传修饰活动。尽管取得了这些令人鼓舞的成果， 前列腺炎症及相关疾病的表观基因组变化和潜在的表观遗传学机制 疾病，包括前列腺癌（PCa）和CAM产品如何表观遗传修饰的炎症 导致这些异常过程的抑制的表观基因组仍然未知。根据我们初步的 研究和以前发表的报告，我们假设慢性炎症过程将驱动 炎症表观基因组和CAM产物的变化将修饰这些炎症表观基因组， 改变导致抑制炎症及其相关疾病，包括癌症， 前列腺有三个特定的目的：（1）研究I3C赋予的表观基因组改变， 三萜类UA在预防Pten-/-、PhiP-hCYP 1A和 （2）确定I3C和I4C引起的预防效果和表观遗传学改变， 三萜类化合物UA在NCr（-/-）小鼠中的人前列腺VCaP异种移植物中的作用;以及（3）阐明体外 炎症/氧化应激和促凋亡基因调控的表观遗传机制 通过DIM和三萜类UA在TRAMP C1、Pten-CaP2、VCaP和 LNCaP细胞培养系统。更好地理解CAM产品的表观遗传机制 抑制炎症及其相关疾病将开辟新的途径， 治疗人类慢性炎性疾病，包括前列腺癌。

Excessive and chronic inflammation can contribute to many acute and chronic diseases including autoimmune disease, neurological, cardiovascular disease, and cancer. Increasing evidence suggests that chronic inflammation is closely associated with epigenetic alterations, mediated by DNA and histone modifications, driving changes in the expression of many inflammatory genes, such as IL1R1, IL-1β, toll-like receptor 2, 15-LOX, COX-2, CXCL14, CCL25, CXCL6, IL13, IL17C and IL4R. Importantly several classes of natural CAM products including indole-3-carbinol and triterpenoids possess antiinflammatory and epigenetic-modifying properties. Our Preliminary Studies show that: (1) the epigenetic CpG methylation status of inflammatory genes were altered in TRAMP prostate tumor as compared to the wild type control using MeDIP-seq technology; (2) in 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced inflammation/high-grade PIN (HGP) in the prostate of CYP1A-humanized mice, inflammatory markers such as 8-oxo-dG, nitrotyrosine, COX-2, p-AKT, and PTEN were increased; (3) inflammatory infiltrates were increased in mouse prostate specific Pten-/- HGP; and (4) Indole-3-carbinol (I3C)/3,3'-diindolylmethane (DIM) from cruciferous vegetables and triterpenoid ursolic acid (UA) from medicinal plants, fruits and vegetables such as blueberries, cranberry, beets, and mushrooms, which possess potent anti-inflammatory activities in different types of cells, were found to trigger epigenetics modifying activities. Despite these promising results, the epigenomic changes and the underlying epigenetics mechanisms of prostate inflammation and related diseases including prostate cancer (PCa) and how CAM products epigenetically modified the inflammatory epigenome leading to inhibition of these aberrant processes remains unknown. Based on our preliminary studies and previous published reports, we hypothesize that chronic inflammatory processes would drive changes of inflammatory epigenome and CAM products would modify these inflammatory epigenomic alterations resulting in suppression of inflammation and its related diseases including cancer in the prostate with three Specific Aims: (1) To investigate the epigenome alterations imparted by I3C and triterpenoid UA in prevention of prostate inflammation and carcinogenesis in Pten-/-, PhiP-hCYP1A and TRAMP mice; (2) To determine the preventive efficacy and epigenetic alterations elicited by I3C and triterpenoid UA in human prostate VCaP xenograft in NCr(-/-) mice; and (3) To elucidate the in vitro epigenetic mechanisms of regulation of the inflammatory/oxidative stress and pro-apoptotic genes obtained from in vivo Aims 1 and 2 by DIM and triterpenoid UA in TRAMP C1, Pten-CaP2, VCaP and LNCaP cell culture system. Better understanding of the epigenetics mechanisms of how CAM products inhibit inflammation and its related disease would open new avenue of approaches for the prevention and treatment of chronic inflammatory diseases including the PCa in human.