Peroxisome Proliferator-activated Receptor β (δ)-dependent Regulation of Ubiquitin C Expression Contributes to Attenuation of Skin Carcinogenesis

Abstract The role of peroxisome proliferator-activated receptor-β (PPARβ) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPARβ-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPARβ-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARβ-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPARβ regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARβ. These results strongly suggest that activation of PPARβ-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.