Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Chemical phylogenetics of histone deacetylases

Nature Chemical Biology volume 6, pages 238–243 (2010)Cite this article

Subjects

Abstract

The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development of a platform for biochemical profiling of human deacetylases.
Figure 2: Chemical phylogenetic analysis of HDACs identifies unexpected selectivity of HDAC inhibitors.
Figure 3: Inhibition of class IIa HDACs by acetylated lysine-based substrates.
Figure 4: Synthesis and testing of an HDAC-biased chemical library and identification of a nonselective HDAC inhibitor.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

Swiss-Prot

References

  1. Minucci, S. & Pelicci, P.G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 6, 38–51 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Lee, K.K. & Workman, J.L. Histone acetyltransferase complexes: one size doesn′t fit all. Nat. Rev. Mol. Cell Biol. 8, 284–295 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Gregoretti, I.V., Lee, Y.M. & Goodson, H.V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Smith, B.C., Hallows, W.C. & Denu, J.M. Mechanisms and molecular probes of sirtuins. Chem. Biol. 15, 1002–1013 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sternson, S.M., Wong, J.C., Grozinger, C.M. & Schreiber, S.L. Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. Org. Lett. 3, 4239–4242 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Bowers, A.A. et al. Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole. J. Am. Chem. Soc. 131, 2900–2905 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bolden, J.E., Peart, M.J. & Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Jones, P. et al. Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. Bioorg. Med. Chem. Lett. 18, 1814–1819 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Zhou, X., Richon, V.M., Rifkind, R.A. & Marks, P.A. Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. Proc. Natl. Acad. Sci. USA 97, 1056–1061 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Parra, M., Kasler, H., McKinsey, T.A., Olson, E.N. & Verdin, E. Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. J. Biol. Chem. 280, 13762–13770 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Mottet, D. et al. Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ. Res. 101, 1237–1246 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Renthal, W. et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56, 517–529 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Tsankova, N.M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9, 519–525 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Bolger, T.A. & Yao, T.P. Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J. Neurosci. 25, 9544–9553 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cohen, T.J. et al. The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. J. Biol. Chem. 282, 33752–33759 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Bowers, A. et al. Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. J. Am. Chem. Soc. 130, 11219–11222 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Riester, D., Wegener, D., Hildmann, C. & Schwienhorst, A. Members of the histone deacetylase superfamily differ in substrate specificity towards small synthetic substrates. Biochem. Biophys. Res. Commun. 324, 1116–1123 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Lahm, A. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. USA 104, 17335–17340 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wong, J.C., Sternson, S.M., Louca, J.B., Hong, R. & Schreiber, S.L. Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes. Chem. Biol. 11, 1279–1291 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Vegas, A.J. et al. Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors. Angew. Chem. Int. Edn Engl. 46, 7960–7964 (2007).

    Article  CAS  Google Scholar 

  22. Patel, V. et al. Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum. J. Med. Chem. 52, 2185–2187 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, D., Helquist, P. & Wiest, O. Zinc binding in HDAC inhibitors: a DFT study. J. Org. Chem. 72, 5446–5449 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Schuetz, A. et al. Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J. Biol. Chem. 283, 11355–11363 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bottomley, M.J. et al. Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J. Biol. Chem. 283, 26694–26704 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mujtaba, S., Zeng, L. & Zhou, M.M. Structure and acetyl-lysine recognition of the bromodomain. Oncogene 26, 5521–5527 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Katoh, K., Kuma, K., Toh, H. & Miyata, T. MAFFT version 5: improvement in accuracy of multiple sequence alignment. Nucleic Acids Res. 33, 511–518 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Katoh, K., Misawa, K., Kuma, K. & Miyata, T. MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. Nucleic Acids Res. 30, 3059–3066 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Katoh, K. & Toh, H. Recent developments in the MAFFT multiple sequence alignment program. Brief. Bioinform. 9, 286–298 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, L.S. et al. The impact of multiple protein sequence alignment on phylogenetic estimation. in IEEE/ACM Transactions on Computational Biology and Bioinformatics (IEEE Computer Society, 2009) 〈http://doi.ieeecomputersociety.org/10.1109/TCBB.2009.68〉.

  31. Stamatakis, A., Hoover, P. & Rougemont, J. A rapid bootstrap algorithm for the RAxML Web servers. Syst. Biol. (Stevenage) 57, 758–771 (2008).

    Article  Google Scholar 

Download references

Acknowledgements

We thank S. Schreiber and the Broad Chemical Biology Program for research space and support. We thank J. Clardy, T. Mitchison, R. Weissleder, O. Wiest, R. Williams (Colorado State University), T. Lewis (Broad Institute) and R. Maglathlin (Broad Institute) for support, thoughtful discussions and access to key instrumentation and reagents. We thank A. Stamatakis for helpful discussions on phylogenetics. We thank C. Johnson, G. Beletsky and S. Jonston for analytical support. This work was supported by grants from the US National Cancer Institute (1K08CA128972; J.E.B.), the American Society of Hematology (J.E.B.), the Multiple Myeloma Research Foundation (J.E.B.), the Burroughs-Wellcome Foundation (J.E.B.), the US National Institutes of Health (T32CA079443 to M.L.G., 1R01DA028301-01 to S.J.H. and P01CA078048 to R.M.), and the US National Science Foundation (DEB 0733029 and ITR 0331453 to T.W.). The project has been funded in part with funds from the US National Cancer Institute's Initiative for Chemical Genetics (contract number N01-CO-12400). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    James E Bradner, Nathan West & Edward F Greenberg

  2. Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    James E Bradner, Nathan West, Edward F Greenberg, Stephen J Haggarty & Ralph Mazitschek

  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    James E Bradner

  4. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Melissa L Grachan & Ralph Mazitschek

  5. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Stephen J Haggarty

  6. Department of Computer Sciences, University of Texas, Austin, Texas, USA

    Tandy Warnow

  7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Ralph Mazitschek

Authors
  1. James E Bradner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathan West
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melissa L Grachan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward F Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen J Haggarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tandy Warnow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ralph Mazitschek
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.E.B. developed biochemical methods, analyzed data, designed and synthesized the cinnamic hydroxmate library, provided research funding, supervised, prepared the manuscript and mentored N.W., M.L.G. and E.F.G. N.W. developed the class IIa biochemical methods, analyzed data and synthesized pandacostat. M.L.G. synthesized and purified pandacostat and analyzed data. E.F.G. developed the class I and IIb biochemical methods and analyzed data. S.J.H. designed experiments and provided reagents. T.W. advised on phylogenetic analysis. R.M. designed and synthesized substrates and tool HDAC inhibitors, synthesized the cinnamic hydroxmate library, developed methods, analyzed data, provided research funding, prepared the manuscript, and mentored M.L.G. The corresponding authors (J.E.B. and R.M.) certify that all authors have agreed to all the content in the manuscript, including the data as presented.

Corresponding authors

Correspondence to James E Bradner or Ralph Mazitschek.

Ethics declarations

Competing interests

J.E.B. and R.M. are scientific founders of and shareholders in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–8 and Supplementary Table 1 (PDF 3935 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bradner, J., West, N., Grachan, M. et al. Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6, 238–243 (2010). https://doi.org/10.1038/nchembio.313

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.313

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing