title: The epigenetic effects of aspirin: the modification of histone H3 lysine 27 acetylation in the prevention of colon carcinogenesis in azoxymethane- and dextran sulfate sodium-treated CF-1 mice.
abstract: Colorectal cancer (CRC) is the third most common cancer worldwide. Chronic inflammation appears to enhance the risk of CRC. Emerging evidence has suggested that epigenetic mechanisms play an important role in CRC. Aspirin [acetylsalicylic acid (ASA)] has been shown to prevent CRC; however, the epigenetic mechanisms of its action remain unknown. This study investigated the protective role of ASA in azoxymethane (AOM)-initiated and dextran sulfate sodium (DSS)-promoted colitis-associated colon cancer (CAC) and examined the epigenetic effects, particularly on histone 3 lysine 27 acetylation (H3K27ac), underlying the preventive effect of ASA. CF-1 mice were fed with AIN-93M diet with or without 0.02% ASA from 1 week prior to AOM initiation until the mice were killed 20 weeks after AOM injection. Our results showed that AOM/DSS + ASA significantly suppressed inflammatory colitis symptoms and tumor multiplicity. AOM/DSS + ASA reduced AOM/DSS-induced protein expression and the activity of histone deacetylases (HDACs) and globally restored H3K27ac. Furthermore, AOM/DSS + ASA inhibited AOM/DSS-induced enrichment of H3K27ac in the promoters of inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) that corresponded to the dramatic suppression of the messenger RNA (mRNA) and protein levels. Surprisingly, no significant changes in the H3K27ac abundance in the prostaglandin-endoperoxide synthase 2 (Cox-2) promoters or in the Cox-2 mRNA and protein expression were observed. Collectively, our results suggest that a potential novel epigenetic mechanism underlies the chemopreventive effects of ASA, and this mechanism attenuates CAC in AOM/DSS-induced CF-1 mice via the inhibition of HDACs and the modification of H3K27ac marks that suppress iNOS, TNF-α and IL-6.
authors.affiliation: Graduate Program in Pharmaceutical Sciences.|Department of Pharmaceutics and.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Graduate Program in Pharmaceutical Sciences.|Department of Pharmaceutics and.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Chungli City, Taoyuan 32023, Taiwan and.
authors.forename: Zheng-Yuan
authors.initials: ZY
authors.lastname: Su
authors.affiliation: Department of Pharmaceutics and.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Wenji
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Chemical Biology, Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Mou-Tuan
authors.initials: MT
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics and.|Center for Epigenomics of CAM Natural Products, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Ah-Ng
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental; D052247:Nitric Oxide Synthase Type II / Q000235:genetics
chemical_list: D016588:Anticarcinogenic Agents; D006657:Histones; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D006655:Histone Deacetylases; D008239:Lysine; D001397:Azoxymethane; D001241:Aspirin