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

Vladimir Petrovic1, Robert H Costa, Lester F Lau

  • 1Department of Biochemistry & Molecular Genetics, University of Illinois, College of Medicine, Chicago, IL, USA.

Cancer Biology & Therapy
|April 8, 2010
PubMed

Insights

Thiazolidinediones (TZDs) inhibit the transcription factor FoxM1, crucial for cancer cell growth. This occurs via suppression of Sp1, offering a new therapeutic strategy for targeting FoxM1 in tumors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • FoxM1 (Forkhead Box transcription factor) drives cell cycle progression and is vital in liver, lung, prostate, and colorectal tumor development.
  • Thiazolidinediones (TZDs) are known activators of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor transcription factor.

Purpose of the Study:

  • To investigate the mechanism by which TZDs inhibit FoxM1 gene expression.
  • To explore the role of Sp1 transcription factor in FoxM1 regulation and TZD-mediated effects.

Main Methods:

  • Treatment of human hepatoma cell lines (HepG2, PLC/PRF/5) with TZDs.
  • Analysis of FoxM1 promoter for PPARγ/retinoid X receptor (RXR) binding sites.
  • Knockdown of PPARγ.
  • Investigation of Sp1 binding to the FoxM1 promoter.
  • Treatment with mithramycin, an Sp1 inhibitor.

Main Results:

  • TZDs significantly inhibited FoxM1 gene expression in hepatoma cells.
  • No PPARγ/RXR binding sites were found in the FoxM1 promoter, and PPARγ knockdown did not affect TZD-mediated FoxM1 downregulation.
  • Sp1 was identified as a positive regulator of FoxM1 transcription, binding to its promoter region.
  • Mithramycin inhibited FoxM1 expression, confirming Sp1's role.
  • TZD-induced suppression of Sp1 activity was identified as the mechanism for FoxM1 downregulation.

Conclusions:

  • TZDs suppress FoxM1 gene expression by inhibiting the Sp1 transcription factor.
  • This mechanism provides a novel pathway for TZD-mediated inhibition of cancer cell growth.
  • Targeting FoxM1 activity in cancer cells can be achieved using PPARγ agonists or mithramycin.

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