title: Chromatin remodeling by curcumin alters endogenous aryl hydrocarbon receptor signaling.
abstract: The aim of this study was to gain more information about the mechanisms that regulate expression of the aryl hydrocarbon receptor (AHR) target gene CYP1A1. Human hepatoma cells (HepG2 and Huh7) and human immortalized keratinocytes (HaCaT) were treated with different concentrations of the dietary polyphenolic compound curcumin (CUR) alone or in combination with the natural AHR agonist 6-formylindolo[3,2-b]carbazole (FICZ). In an earlier study, we described that CUR can activate the AHR indirectly by inhibiting metabolic clearance of FICZ. Here, we measured cell viability, activation of AHR signaling, oxidative stress and histone modifying activities in response to CUR at concentrations ranging from 0.1 to 50 μM. We observed apparent non-linear responses on cell viability and activation of AHR signaling. The CYP1A1 expression and the CYP1A1 enzyme activity in the presence of CUR reflected the histone acetylation efficiency observed in nuclear extracts. At the lowest concentration, CUR significantly decreased histone deacetylase activity and increased the FICZ-induced CYP1A1 activity. In contrast, at the highest concentration, CUR increased the formation of reactive oxygen species, significantly inhibited histone acetylation, and temporally decreased FICZ-induced CYP1A1 activity. The results suggest that CUR can both increase and decrease the accessibility of DNA and thereby influence transcriptional responses to the ligand-activated AHR. This suggestion was supported by the fact that chromatin remodeling treatments with trichostatin A, p300, or 5-aza-dC increased CYP1A1 transcription. We conclude that the AHR-dependent transcriptional efficiency is modified by factors that influence the cellular redox status and the chromatin structure.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Fars 71345-1583, Iran.
authors.forename: Afshin
authors.initials: A
authors.lastname: Mohammadi-Bardbori
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Fars 71345-1583, Iran.
authors.forename: Amin Reza
authors.initials: AR
authors.lastname: Akbarizadeh
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Fars 71345-1583, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Delju
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Agneta.Rannug@ki.se.
authors.forename: Agneta
authors.initials: A
authors.lastname: Rannug
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D003474:Curcumin
keywords: Aryl hydrocarbon receptor; CYP1A1; Curcumin; Epigenetic; FICZ