Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin.

The Forkhead Box transcription factor FoxM1 regulates expression of genes that promote cell cycle progression, and it plays essential roles in the development of liver, lung, prostate and colorectal tumors. Thiazolidinediones (TZDs) activate the peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated nuclear receptor transcription factor. We found that treatment of the human hepatoma cell lines HepG2 and PLC/PRF/5 cells with TZDs leads to inhibition of FoxM1 gene expression. No PPAR gamma/retinoid X receptor (RXR) consensus DNA binding sites were detected in the FoxM1 promoter extending to - 10 kb upstream, and knockdown of PPAR gamma had no impact on TZD mediated downregulation of FoxM1 expression. Previously, others showed that PPAR gamma agonists inhibit the expression and DNA-binding activity of the Sp1 transcription factor. Here we show that Sp1 binds to the FoxM1 promoter region and positively regulates FoxM1 transcription, while mithramycin, a chemotherapy drug that specifically binds GC rich sequences in the DNA and inhibits activities of Sp1, inhibits expression of FoxM1. Our data suggest that TZD mediated suppression of Sp1 is responsible for downregulation of FoxM1 gene expression. Inhibition of FoxM1 expression by TZDs provides a new mechanism for TZD mediated negative regulation of cancer cell growth. FoxM1 expression and activity in cancer cells can be targeted using PPAR gamma agonists or the anti-neoplastic antibiotic mithramycin.