title: Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in keratinocytes.
abstract: Whether peroxisome proliferator-activated receptor β/δ (PPARβ/δ) reduces skin tumorigenesis by altering aryl hydrocarbon receptor (AHR)-dependent activities was examined. Polycyclic aromatic hydrocarbons (PAH) increased expression of cytochrome P4501A1 (CYP1A1), CYP1B1 and phase II xenobiotic metabolizing enzymes in wild-type skin and keratinocytes. Surprisingly, this effect was not found in Pparβ/δ-null skin and keratinocytes. Pparβ/δ-null keratinocytes exhibited decreased AHR occupancy and histone acetylation on the Cyp1a1 promoter in response to a PAH compared with wild-type keratinocytes. Bisulfite sequencing of the Cyp1a1 promoter and studies using a DNA methylation inhibitor suggest that PPARβ/δ promotes demethylation of the Cyp1a1 promoter. Experiments with human HaCaT keratinocytes stably expressing shRNA against PPARβ/δ also support this conclusion. Consistent with the lower AHR-dependent activities in Pparβ/δ-null mice compared with wild-type mice, 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis was inhibited in Pparβ/δ-null mice compared with wild-type. Results from these studies demonstrate that PPARβ/δ is required to mediate complete carcinogenesis by DMBA. The mechanisms underlying this PPARβ/δ-dependent reduction of AHR signaling by PAH are not due to alterations in the expression of AHR auxiliary proteins, ligand binding or AHR nuclear translocation between genotypes, but are likely influenced by PPARβ/δ-dependent demethylation of AHR target gene promoters including Cyp1a1 that reduces AHR accessibility as shown by reduced promoter occupancy. This PPARβ/δ/AHR crosstalk is unique to keratinocytes and conserved between mice and humans.
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and The Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Borland
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and.
authors.forename: Prasad
authors.initials: P
authors.lastname: Krishnan
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and.
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and.
authors.forename: Prajakta P
authors.initials: PP
authors.lastname: Albrecht
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and.
authors.forename: Moses T
authors.initials: MT
authors.lastname: Bility
authors.affiliation: Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Marcus
authors.affiliation: Department of Pharmacology, Penn State Cancer Institute, The Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA 17033, USA and.
authors.forename: Jyh M
authors.initials: JM
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Penn State Cancer Institute, The Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA 17033, USA and.
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and The Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis and The Graduate Program in Biochemistry, Microbiology, and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA, jmp21@psu.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000502:physiology*; D048068:PPAR-beta / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D051792:Basic Helix-Loop-Helix Proteins; D002273:Carcinogens; D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse