Peroxisome Proliferator-activated Receptor γ Agonists Induce Cell Cycle Arrest through Transcriptional Regulation of Kruppel-like Factor 4 (KLF4)

Peroxisome proliferator-activated receptor gamma(PPAR gamma), a sub-group of ligand-activated nuclear receptors, plays critical roles in cell cycle regulation, differentiation, apoptosis, and invasion. PPAR gamma is involved in tumorigenesis and is a potent target for cancer therapy. PPAR gamma transactivation of KLF4 has been demonstrated in various studies; however, how PPAR gamma regulates KLF4 expression is not clear. In this study, we reveal that PPAR gamma regulates the expression of KLF4 by binding directly to the PPAR response element (PPRE) within the KLF4 promoter. The PPRE resides at - 1657 to - 1669 bp upstream of the KLF4 ATG codon, which is essential for the transactivation of troglitazone-induced KLF4 expression. Furthermore, we found that stable silencing of KLF4 obviously suppressed the G(1)/S arrest and anti-proliferation effects induced by PPAR gamma ligands. Taken together, our data indicate that up-regulation of KLF4 upon PPAR gamma activation is mediated through the PPRE in the KLF4 promoter, thus providing further insights into the PPAR gamma signal transduction pathway as well as a novel cancer therapeutic strategy.