Excessive and chronic inflammation can contribute to many acute andchronic diseases including autoimmune disease, neurological, cardiovascular disease, and cancer. Increasingevidence suggests that chronic inflammation is closely associated with epigenetic alterations, mediated byDNA and histone modifications, driving changes in the expression of many inflammatory genes, such asIL1R1, IL-1β, toll-like receptor 2, 15-LOX, COX-2, CXCL14, CCL25, CXCL6, IL13, IL17C and IL4R. Importantlyseveral classes of natural CAM products including indole-3-carbinol and triterpenoids possess antiinflammatoryand epigenetic-modifying properties. Our Preliminary Studies show that: (1) the epigenetic CpGmethylation status of inflammatory genes were altered in TRAMP prostate tumor as compared to the wild typecontrol using MeDIP-seq technology; (2) in 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-inducedinflammation/high-grade PIN (HGP) in the prostate of CYP1A-humanized mice, inflammatory markers such as8-oxo-dG, nitrotyrosine, COX-2, p-AKT, and PTEN were increased; (3) inflammatory infiltrates were increasedin mouse prostate specific Pten-/- HGP; and (4) Indole-3-carbinol (I3C)/3,3'-diindolylmethane (DIM) fromcruciferous vegetables and triterpenoid ursolic acid (UA) from medicinal plants, fruits and vegetables such asblueberries, cranberry, beets, and mushrooms, which possess potent anti-inflammatory activities in differenttypes of cells, were found to trigger epigenetics modifying activities. Despite these promising results, theepigenomic changes and the underlying epigenetics mechanisms of prostate inflammation and relateddiseases including prostate cancer (PCa) and how CAM products epigenetically modified the inflammatoryepigenome leading to inhibition of these aberrant processes remains unknown. Based on our preliminarystudies and previous published reports, we hypothesize that chronic inflammatory processes would drivechanges of inflammatory epigenome and CAM products would modify these inflammatory epigenomicalterations resulting in suppression of inflammation and its related diseases including cancer in theprostate with three Specific Aims: (1) To investigate the epigenome alterations imparted by I3C andtriterpenoid UA in prevention of prostate inflammation and carcinogenesis in Pten-/-, PhiP-hCYP1A andTRAMP mice; (2) To determine the preventive efficacy and epigenetic alterations elicited by I3C andtriterpenoid UA in human prostate VCaP xenograft in NCr(-/-) mice; and (3) To elucidate the in vitroepigenetic mechanisms of regulation of the inflammatory/oxidative stress and pro-apoptotic genesobtained from in vivo Aims 1 and 2 by DIM and triterpenoid UA in TRAMP C1, Pten-CaP2, VCaP andLNCaP cell culture system. Better understanding of the epigenetics mechanisms of how CAM productsinhibit inflammation and its related disease would open new avenue of approaches for the prevention andtreatment of chronic inflammatory diseases including the PCa in human.
|Effective start/end date||9/15/15 → 8/31/20|
- National Institutes of Health (NIH)
Toll-Like Receptor 2