| First Author | Borland MG | Year | 2014 |
| Journal | Carcinogenesis | Volume | 35 |
| Issue | 7 | Pages | 1602-12 |
| PubMed ID | 24639079 | Mgi Jnum | J:211686 |
| Mgi Id | MGI:5575848 | Doi | 10.1093/carcin/bgu067 |
| Citation | Borland MG, et al. (2014) Modulation of aryl hydrocarbon receptor (AHR)-dependent signaling by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) in keratinocytes. Carcinogenesis 35(7):1602-12 |
| abstractText | Whether peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) 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 Pparbeta/delta-null skin and keratinocytes. Pparbeta/delta-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 PPARbeta/delta promotes demethylation of the Cyp1a1 promoter. Experiments with human HaCaT keratinocytes stably expressing shRNA against PPARbeta/delta also support this conclusion. Consistent with the lower AHR-dependent activities in Pparbeta/delta-null mice compared with wild-type mice, 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumorigenesis was inhibited in Pparbeta/delta-null mice compared with wild-type. Results from these studies demonstrate that PPARbeta/delta is required to mediate complete carcinogenesis by DMBA. The mechanisms underlying this PPARbeta/delta-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 PPARbeta/delta-dependent demethylation of AHR target gene promoters including Cyp1a1 that reduces AHR accessibility as shown by reduced promoter occupancy. This PPARbeta/delta/AHR crosstalk is unique to keratinocytes and conserved between mice and humans. |
