The transcription factor FOXM1 is a cellular target of the natural product thiostrepton

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  • An Erratum to this article was published on 23 September 2011

Abstract

Transcription factors are proteins that bind specifically to defined DNA sequences to promote gene expression. Targeting transcription factors with small molecules to modulate the expression of certain genes has been notoriously difficult to achieve. The natural product thiostrepton is known to reduce the transcriptional activity of FOXM1, a transcription factor involved in tumorigenesis and cancer progression. Herein we demonstrate that thiostrepton interacts directly with FOXM1 protein in the human breast cancer cells MCF-7. Biophysical analyses of the thiostrepton–FOXM1 interaction provide additional insights on the molecular mode of action of thiostrepton. In cellular experiments, we show that thiostrepton can inhibit the binding of FOXM1 to genomic target sites. These findings illustrate the potential druggability of transcription factors and provide a molecular basis for targeting the FOXM1 family with small molecules.

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Figure 1: Chemical modification of thiostrepton (1) and biological evaluation.
Figure 2: Identification of FOXM1 as a molecular target for the natural product thiostrepton (1).
Figure 3: Biophysical evaluation of thiostrepton–FOXM1 interactions.
Figure 4: Thiostrepton (1) prevents FOXM1 binding to the promoter/enhancer regions of cell cycle regulatory genes.

Change history

  • 05 September 2011

    In the version of this Article originally published, the corresponding author should have been listed as Shankar Balasubramanian. However, the email address was correct. This error has been corrected in the HTML and PDF versions of the Article.

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Acknowledgements

We thank R. Kranaster, P. Sledz and C. Ross-Innes for discussions and advice and C. D'Santos for mass spectrometry analysis and C. Lowe for proof-reading the manuscript. We thank the Cambridge Commonwealth Trust and Trinity College, Cambridge, for a studentship (N.H.) and the Biotechnology and Biological Sciences Research Council for grant funding. S.B.'s laboratory is supported by programme funding from Cancer Research UK. R.R. is a Herchel Smith Research Fellow.

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All authors conceptualized this study, designed the experiments, analysed the data and wrote the manuscript. N.H. and D.A.S. performed the experiments.

Correspondence to Shankar Balasubramanian.

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The authors declare no competing financial interests.

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Hegde, N., Sanders, D., Rodriguez, R. et al. The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nature Chem 3, 725–731 (2011) doi:10.1038/nchem.1114

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