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[Cancer Research 64, 3701-3713, May 15, 2004]
© 2004 American Association for Cancer Research

Epidemiology and Prevention

Transactivation of the PPAR-Responsive Enhancer Module in Chemopreventive Glutathione S-Transferase Gene by the Peroxisome Proliferator-Activated Receptor-{gamma} and Retinoid X Receptor Heterodimer

Eun Young Park, Il Je Cho and Sang Geon Kim

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea

Cancer chemopreventive agents transcriptionally induce glutathione S-transferase (GST), which can protect cells from chemical-induced carcinogenesis. Activation of either NF-E2-related factor-2 (Nrf2) or the CCAAT/enhancer binding protein-ß (C/EBPß) contributes to GST induction. Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and the retinoic acid X receptor (RXR) play roles in regulating cell differentiation and chemoprevention. This study examined GSTA2 gene induction by the PPAR{gamma} activator and 9-cis-retinoic acid (RA), a RXR ligand, and investigated the molecular basis of PPAR-RXR-mediated GSTA2 induction in the H4IIE hepatocytes. Either 15-deoxy-{delta} (12, 14)-prostaglandin J2 (PGJ2) or RA induced GSTA2 with Nrf2 and C/EBPß activation. When compared with PGJ2 or RA alone, PGJ2 + RA enhanced GSTA2 induction, with increases in Nrf2 and C/EBPß activation. PGJ2 + RA increased the luciferase reporter gene activity in the cells transfected with the –1.65-kb flanking region of the GSTA2 gene. Thiazolidinedione PPAR{gamma} agonists, troglitazone, rosiglitazone, and pioglitazone, in combination with RA, potentiated GSTA2 induction, confirming that the activation of the PPAR{gamma} and RXR heterodimer contributed to GSTA2 expression. Deletion of the antioxidant response element- or C/EBP-binding sites or the overexpression of dominant-negative mutant of C/EBP abolished the reporter gene expression. PGJ2 + RA increased the binding of the PPAR{gamma} – RXR heterodimer to the putative PPAR-response elements (PPREs) in the GSTA2 promoter. Specific mutations of these multiple PPRE sites resulted in the complete loss of its responsiveness to PGJ2 + RA, which suggests that these binding sites function as a PPRE-responsive enhancer module (PPREM). Transactivation of PPREM by the PPAR{gamma} – RXR heterodimer was verified by the effective GSTA2 induction in the cells treated with PGJ2 + RA after transfecting them with the plasmids encoding PPAR{gamma}1 and RXR{alpha}. In conclusion, the PPAR{gamma} – RXR heterodimer promotes GSTA2 induction by activating PPREM in the GSTA2 gene, as well as inducing Nrf2 and C/EBPß activation.




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