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

Yahui Zhao,Huan He,Zhihua Liu,Sheng Li,Qibing Zhou

doi:10.1074/jbc.m111.317487

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ), a subgroup of ligand-activated nuclear receptors, plays critical roles in cell cycle regulation, differentiation, apoptosis, and invasion. PPARγ is involved in tumorigenesis and is a potent target for cancer therapy. PPARγ transactivation of KLF4 has been demonstrated in various studies; however, how PPARγ regulates KLF4 expression is not clear. In this study, we reveal that PPARγ 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 PPARγ ligands. Taken together, our data indicate that up-regulation of KLF4 upon PPARγ activation is mediated through the PPRE in the KLF4 promoter, thus providing further insights into the PPARγ signal transduction pathway as well as a novel cancer therapeutic strategy.

Highlights

peroxisome proliferator-activated receptors (PPARs)␥ serves as a master transcriptional regulator of glucose and lipid metabolism, but it plays an important role in carcinogenesis
We found that stable silencing of KLF4 obviously suppressed the G1/S arrest and anti-proliferation effects induced by PPAR␥ ligands, providing further insights into the PPAR␥ signal transduction pathway as well as a novel cancer therapeutic strategy
WY14643 (PPAR␣ ligand) and GW0742 (PPAR␤ ligand) did not affect KLF4 expression (Fig. 1E). These results indicate that PPAR␥ agonists can induce KLF4 expression, which is consistent with previous reports [25]

Summary

Background

PPAR␥ serves as a master transcriptional regulator of glucose and lipid metabolism, but it plays an important role in carcinogenesis. Our data indicate that up-regulation of KLF4 upon PPAR␥ activation is mediated through the PPRE in the KLF4 promoter, providing further insights into the PPAR␥ signal transduction pathway as well as a novel cancer therapeutic strategy. Line with a tumor suppressor function of KLF4, it has been found that KLF4 is down-regulated by promoter hypermethylation and loss of heterozygosity in colorectal cancer, and its overexpression reduces tumorigenesis in colon cancer cells in vivo [19, 23]. We found that stable silencing of KLF4 obviously suppressed the G1/S arrest and anti-proliferation effects induced by PPAR␥ ligands, providing further insights into the PPAR␥ signal transduction pathway as well as a novel cancer therapeutic strategy

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION