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、神经疾病、心血管疾病和癌症。渐增 有证据表明，慢性炎症与表观遗传改变密切相关，这种改变是由 DNA和组蛋白修饰，推动许多炎症基因表达的变化，如 IL-1R1、IL-1β、Toll样受体2、15-LOX、COX-2、CXCL14、CCL25、CXCL6、IL13、IL17C和IL4R。重要的是 几类天然CAM产品，包括吲哚-3-甲醇和三萜类化合物具有抗炎作用 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，前列腺癌中炎症基因的甲基化状态发生了改变 利用MeDIP-SEQ技术控制；(2)在2-氨基-1-甲基-6-苯基咪唑并[4，5-b]吡啶(PhIP)诱导 CYP1A人源化小鼠前列腺炎性/高级别PIN(HGP)、炎症标志物 8-oxo-DG、硝基酪氨酸、COX-2、p-AKT、PTEN升高；(3)炎性细胞浸润增多 和(4)吲哚-3-甲醇(I3C)/3，3‘-二吲哚甲烷(DIM) 十字花科蔬菜和来自药用植物、水果和蔬菜的三萜熊果酸(UA)，如 蓝莓、小红莓、甜菜和蘑菇，它们在不同的不同部位都具有强大的抗炎活性。 不同类型的细胞，被发现触发表观遗传学修饰活动。尽管有这些令人振奋的结果， 前列腺炎及其相关表观遗传学机制的表观基因组学改变 包括前列腺癌(PCA)在内的疾病以及CAM产品如何表观遗传地改变炎症 导致抑制这些异常过程的表观基因组仍不清楚。根据我们的初步调查 研究和之前发表的报告，我们假设慢性炎症过程将推动 炎症性表观基因组和CAM产物的改变会改变这些炎症性表观基因组 导致炎症及其相关疾病包括癌症的抑制的改变 前列腺有三个特定的目的：(1)研究I3C和I3C对前列腺癌的影响 三萜尿酸对Pten-/-、PhIP-hCyP1a和Pten-/-的前列腺炎症及癌变的预防作用 (2)测定I3C和I3C对小鼠的预防作用和表观遗传学改变。 NCR(-/-)小鼠人前列腺VCaP异种移植中三萜尿酸的研究 炎症/氧化应激和促凋亡基因调控的表观遗传学机制 从活体靶标1和2通过二胺和三萜类尿酸在Tramp C1，Pten-CaP2，VCaP和 LNCaP细胞培养系统。更好地理解CAM产品的表观遗传学机制 抑制炎症及其相关疾病将为预防和治疗癌症开辟新的途径 治疗包括前列腺癌在内的人类慢性炎症性疾病。

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.