Peroxisome proliferator-activated receptor γ is a Zac target gene mediating Zac antiproliferation

Zac is a C2H2 zinc finger protein, which regulates apoptosis and cell cycle arrest through DNA binding and transactivation. During tumorigenesis and in response to mitogenic activation, Zac gene expression is down-regulated in a methylation-sensitive manner. As yet, no target genes have been identified that could explain the potent antiproliferative function of Zac. Here, applying genome-wide expression analysis, we identify peroxisome proliferator-activated receptor gamma (PPAR gamma) as a new bona fide Zac target gene, which is induced by direct Zac binding to the proximal PPAR gamma 1 promoter. We show that in human colon carcinoma cells, ZAC activates expression of PPAR gamma target genes in a PPAR gamma-dependent manner. Moreover, we show that treatment of pituitary tumor cells with octreotide, a somatostatin analogue, leads to Zac induction and subsequent Zac-dependent up-regulation of PPAR gamma, which thereupon mediates part of the antiproliferative activity of Zac. Our work provides a first step toward elucidating a functional relationship between Zac and PPAR gamma that could be relevant to the understanding of tumorigenesis and diabetes as well.