Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in keratinocytes

Michael G. Borland, Prasad Krishnan, Christina Lee, Prajakta P. Albrecht, Weiwei Shan, Moses T. Bility, Craig B. Marcus, Jyh M. Lin, Shantu Amin, Frank J. Gonzalez, Gary H. Perdew, Jeffrey M. Peters

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Whether 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 as compared to wild-type keratinocytes. Bisulfite sequencing of the Cyp1a1 promoter, and studies using a DNA methylation inhibitor suggest that PPARβ/δ promotes de-methylation 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 to wild-type mice, DMBA-induced skin tumorigenesis was inhibited in Pparβ/δ-null mice as compared to 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 is 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 de-methylation 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.

Original languageEnglish (US)
Article numberbgu067
JournalCarcinogenesis
Volume35
Issue number7
DOIs
StatePublished - Jul 2014

All Science Journal Classification (ASJC) codes

  • Cancer Research

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