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

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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.