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

Nature Chemistry volume 3, pages 725–731 (2011)Cite this article

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An Erratum to this article was published on 23 September 2011

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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.

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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.

References

  1. Schreiber, S. L. The small-molecule approach to biology. Chem. Eng. News 81, 51–61 (2003).

    Article  Google Scholar 

  2. Stockwell, B. R. Chemical genetics: ligand-based discovery of gene function. Nat. Rev. Genet. 1, 116–125 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Altmann, K-H. et al. The state of the art of chemical biology. ChemBioChem 10, 16–29 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Tan, D. S. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat. Chem. Biol. 1, 74–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Berg, T. Inhibition of transcription factors with small organic molecules. Curr. Opin. Chem. Biol. 12, 464–471 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Arndt, H-D. Small molecule modulators of transcription. Angew. Chem. Int. Ed. 45, 4552–4560 (2006).

    Article  CAS  Google Scholar 

  7. Gottesfeld, J. M., Neely, L., Trauger, J. W., Baird, E. E. & Dervan, P. B. Regulation of gene expression by small molecules. Nature 387, 202–205 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Kung, A. L. et al. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell. 6, 33–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Ng, P. Y., Tang, Y., Knosp, W. M., Stadler, H. S. & Shaw, J. T. Synthesis of diverse lactam carboxamides leading to the discovery of a new transcription-factor inhibitor. Angew. Chem. Int. Ed. 46, 5352–5355 (2007).

    Article  CAS  Google Scholar 

  10. Verdine, G. L. & Walensky, L. D. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin. Cancer Res. 13, 7264–7270 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bauer, R. A., Wurst, J. M. & Tan, D. S. Expanding the range of ‘druggable’ targets with natural product-based libraries: an academic perspective. Curr. Opin. Chem. Biol. 14, 308–314 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Koehler, A. N. A complex task? Direct modulation of transcription factors with small molecules. Curr. Opin. Chem. Biol. 14, 331–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lai, E. et al. HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 4, 1427–1436 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Weigel, D., Jürgens, G., Küttner, F., Seifert, E. & Jäckle, H. The homeotic gene forkhead encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell 57, 645–658 (1989).

    Article  CAS  PubMed  Google Scholar 

  15. Krupczak-Hollis, K. et al. The mouse forkhead box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev. Biol. 276, 74–88 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Kalin, T. V. et al. Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res. 66, 1712–1720 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Myatt, S. S. & Lam, E. W-F. The emerging roles of forkhead box (Fox) proteins in cancer. Nat. Rev. Cancer 7, 847–859 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Pagano, J. F., Weinstein, M. J., Stout, H. A. & Donovick, R. Thiostrepton, a new antibiotic. I. In vitro studies. Antibiot. Ann. 554–559 (1955/1956).

  19. Vendeputte, J. & Dutcher, J. D. Thiostrepton, a new antibiotic. II. Isolation and chemical characterization. Antibiot. Ann. 560–561 (1955/1956).

  20. Steinberg, B. A., Jambor, W. P. & Suydam, L. O. Thiostrepton, a new antibiotic. III. In vivo studies. Antibiot. Ann. 562–565 (1955/1956).

  21. Bagley, M. C., Dale, J. W., Merritt, E. A. & Xiong, X. Thiopeptide antibiotics. Chem. Rev. 105, 685–714 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Bhat, U. G., Zipfel, P. A., Tyler, D. S. & Gartel, A. L. Novel anticancer compounds induce apoptosis in melanoma cells. Cell Cycle 7, 1851–1855 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Bowling, B. D., Doudican, N., Manga, P. & Orlow, S. J. Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism. Cancer Chemother. Pharmacol. 63, 37–43 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nicolaou, K. C. et al. Discovery of a biologically active thiostrepton fragment. J. Am. Chem. Soc. 127, 15042–15044 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Kwok, J. M. et al. Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol. Cancer Ther. 7, 2022–2032 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Bhat, U. G., Halasi, M. & Gartel, A. L. Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PloS One 4, e5592 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bhat, U. G., Halasi, M. & Gartel, A. L. FoxM1 is a general target for proteasome inhibitors. PloS One 4, e6593 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Schoof, S. et al. Antiplasmodial thiostrepton derivatives: proteasome inhibitors with a dual mode of action. Angew. Chem. Int. Ed. 49, 3317–3321 (2010).

    Article  CAS  Google Scholar 

  29. Zhang, L. et al. Antibiotic susceptibility of mammalian mitochondrial translation. FEBS Lett. 579, 6423–6427 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Halasi, M. & Gartel, A. L. A novel mode of FoxM1 regulation: positive auto-regulatory loop. Cell Cycle 8, 1966–1967 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Leslie, B. J. & Hergenrother, P. J. Identification of the cellular targets of bioactive small organic molecules using affinity reagents. Chem. Soc. Rev. 37, 1347–1360 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Anderson, B., Hodgkin, D. C. & Viswamitra, M. A. The structure of thiostrepton. Nature 225, 233–235 (1970).

    Article  CAS  PubMed  Google Scholar 

  33. Schoof, S., Baumann, S., Ellinger, B. & Arndt, H-D. A fluorescent probe for the 70 S-ribosomal GTPase-associated center. ChemBiochem 10, 242–245 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Wierstral, I. & Alves, J. Despite its strong transactivation domain, transcription factor FOXM1c is kept almost inactive by two different inhibitory domains. Biol. Chem. 387, 963–976 (2006).

    Google Scholar 

  35. Yao, K. M., Sha, M., Lu, Z. & Wong, G. G. Molecular analysis of a novel winged helix protein, WIN. Expression pattern, DNA binding property, and alternative splicing within the DNA binding domain. J. Biol. Chem. 272, 19827–19836 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Block, K. M. et al. Direct inhibition of hypoxia-inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. J. Am. Chem. Soc. 131, 18078–18088 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wierstra, I. & Alves, J. Cyclin E/Cdk2, P/CAF, and E1A regulate the transactivation of the c-myc promoter by FOXM1. Biochem. Biophys. Res. Commun. 368, 107–115 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, I-C. et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell. Biol. 25, 10875–10894 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Leung, T. W. C. et al. Over-expression of FoxM1 stimulates cyclin B1 expression. FEBS Lett. 507, 59–66 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Doisneau-Sixou, S. F. et al. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr. Relat. Cancer 10, 179–186 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Rae, J. M. et al. GREB1 is a critical regulator of hormone dependent breast cancer growth. Breast Cancer Res. Treat. 92, 141–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Gomez, B. P. et al. Human X-Box binding protein-1 confers both estrogen independence and antiestrogen resistance in breast cancer cell lines. FASEB J. 21, 4013–4027 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Hurtado, A., Holmes, K. A., Ross-Innes, C. S., Schmidt, D. & Carroll, J. S. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat. Genet. 43, 27–33 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Schmidt, D. et al. ChIP-seq: using high-throughput sequencing to discover protein–DNA interactions. Methods 48, 240–248 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gemenetzidis, E. et al. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res. 70, 9515–9526 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations

  1. Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK

    Nagaratna S. Hegde, Raphaël Rodriguez & Shankar Balasubramanian

  2. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK

    Deborah A. Sanders & Shankar Balasubramanian

  3. School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK

    Shankar Balasubramanian

Authors
  1. Nagaratna S. Hegde
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Contributions

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

Corresponding author

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). https://doi.org/10.1038/nchem.1114

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