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

Michael G Borland1, Prasad Krishnan2, Christina Lee2

  • 1Department 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.

Carcinogenesis
|March 19, 2014
PubMed

Insights

Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is essential for skin tumorigenesis by promoting aryl hydrocarbon receptor (AHR) signaling via Cyp1a1 promoter demethylation.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Cancer Research

Background:

  • Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) role in skin tumorigenesis is unclear.
  • Aryl hydrocarbon receptor (AHR) signaling is implicated in skin cancer development.
  • Polycyclic aromatic hydrocarbons (PAHs) activate AHR signaling.

Purpose of the Study:

  • To investigate if PPARβ/δ reduces skin tumorigenesis by modulating AHR-dependent activities.
  • To elucidate the molecular mechanisms underlying PPARβ/δ and AHR crosstalk in skin.

Main Methods:

  • Comparison of gene expression and AHR activity in wild-type and Pparβ/δ-null mouse skin and keratinocytes.
  • Analysis of AHR occupancy and histone acetylation on the Cyp1a1 promoter.
  • Bisulfite sequencing and DNA methylation inhibitor studies to assess promoter methylation.
  • Experiments using human HaCaT keratinocytes with PPARβ/δ knockdown.
  • Assessment of 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis in mice.

Main Results:

  • PAHs induced CYP1A1, CYP1B1, and phase II enzymes in wild-type but not Pparβ/δ-null skin.
  • Pparβ/δ-null keratinocytes showed reduced AHR occupancy and histone acetylation on the Cyp1a1 promoter.
  • PPARβ/δ promotes Cyp1a1 promoter demethylation, reducing AHR accessibility.
  • DMBA-induced skin tumorigenesis was significantly inhibited in Pparβ/δ-null mice.
  • PPARβ/δ/AHR crosstalk mechanisms do not involve AHR auxiliary proteins, ligand binding, or nuclear translocation.

Conclusions:

  • PPARβ/δ is required for DMBA-induced skin carcinogenesis.
  • PPARβ/δ mediates AHR signaling in keratinocytes, in part, by demethylating target gene promoters like Cyp1a1.
  • This PPARβ/δ-dependent regulation of AHR signaling is crucial for skin tumor development and is conserved in humans.

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