Inhibition of Histone Deacetylases

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 791)

Abstract

Lysine acetylation of histones is one of the major epigenetic regulators of chromatin conformation and gene expression. The dynamic nature of histone acetylation is determined by the counterbalancing activity of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Acetylation of histones is generally associated with open and transcriptionally active chromatin, whereas the activity of HDACs leads to histone deacetylation, condensation of chromatin, and inhibition of transcription. Aberrant silencing of tumor suppressors and other genes has been found in different types of cancer. Abnormal activity of HDACs has been implicated in tumorigenesis and therefore considerable effort has been put into the development of HDAC inhibitors as a means of modifying histone acetylation status and reexpressing aberrantly silenced tumor suppressor genes. This has led to the generation of a number of structurally diverse compounds that can effectively inhibit HDAC activity, thus altering chromatin structure in cancer cells. This unit discusses the methods and recent technological developments with respect to the studies of HDAC inhibition in cancer.

Key words

Histone deacetylases Histone acetyltransferases HDAC inhibitors Epigenetic gene silencing Chromatin remodeling 

References

  1. 1.
    Feinberg, A. P. and Tycko, B. (2004) The history of cancer epigenetics. Nat Rev Cancer. 4, 143–153.PubMedCrossRefGoogle Scholar
  2. 2.
    Jones, P. A. and Baylin, S. B. (2007) The epigenomics of cancer. Cell 128, 683–692.PubMedCrossRefGoogle Scholar
  3. 3.
    Jenuwein, T. and Allis, C. D. (2001) Translating the histone code. Science 293, 1074–1080.PubMedCrossRefGoogle Scholar
  4. 4.
    Ho, L. and Crabtree, G. R. (2010) Chromatin remodelling during development. Nature 463, 474–484.PubMedCrossRefGoogle Scholar
  5. 5.
    Minucci, S. and Pelicci, P. G. (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 6, 38–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Marson, C. M. (2009) Histone deacetylase inhibitors: design, structure-activity relationships and therapeutic implications for cancer. Anticancer Agents Med Chem. 9, 661–692.PubMedGoogle Scholar
  7. 7.
    Khan, O. and La Thangue, N. B. (2008) Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas. Nat. Clin. Pract. Oncol. 5, 714–726.PubMedCrossRefGoogle Scholar
  8. 8.
    Marks, P. A., Richon, V. M., Miller, T. and Kelly, W. K. (2004) Histone deacetylase inhibitors. Adv.Cancer. Res. 91, 137–168.PubMedCrossRefGoogle Scholar
  9. 9.
    Ficner, R. (2009) Novel structural insights into class I and II histone deacetylases. Curr Top. Med. Chem. 9, 235–240.PubMedCrossRefGoogle Scholar
  10. 10.
    Bradner, J. E., West, N., Grachan, M. L., Greenberg, E. F., Haggarty, S. J., Warnow, T. and Mazitschek, R. (2010) Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238–243.PubMedCrossRefGoogle Scholar
  11. 11.
    Schuetz, A., Min, J., Allali-Hassani, A., Schapira, M., Shuen, M., Loppnau, P., Mazitschek, R., Kwiatkowski, N. P., Lewis, T. A., Maglathin, R. L., McLean, T. H., Bochkarev, A., Plotnikov, A. N., Vedadi, M. and Arrowsmith, C. H. (2008) Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J. Biol. Chem. 283, 11355–11363.PubMedCrossRefGoogle Scholar
  12. 12.
    Stimson, L., Wood, V., Khan, O., Fotheringham, S. and La Thangue, N. B. (2009) HDAC inhibitor-based therapies and haematological malignancy. Ann Oncol. 20, 1293–1302.PubMedCrossRefGoogle Scholar
  13. 13.
    Marks, P. A. and Breslow, R. (2007) Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 25, 84–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Marks, P. A. and Xu, W. S. (2009) Histone deacetylase inhibitors: Potential in cancer therapy. J. Cell. Biochem. 107, 600–608.PubMedCrossRefGoogle Scholar
  15. 15.
    Campas-Moya, C. (2009) Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc) 45, 787–795.Google Scholar
  16. 16.
    Nebbioso, A., Clarke, N., Voltz, E., Germain, E., Ambrosino, C., Bontempo, P., Alvarez, R., Schiavone, E. M., Ferrara, F., Bresciani, F., Weisz, A., de Lera, A. R., Gronemeyer, H. and Altucci, L. (2005) Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat. Med. 11, 77–84.PubMedCrossRefGoogle Scholar
  17. 17.
    Peart, M. J., Smyth, G. K., van Laar, R. K., Bowtell, D. D., Richon, V. M., Marks, P. A., Holloway, A. J. and Johnstone, R. W. (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc. Natl. Acad. Sci. U. S. A. 102, 3697–3702.PubMedCrossRefGoogle Scholar
  18. 18.
    Keen, J. C., Yan, L., Mack, K. M., Pettit, C., Smith, D., Sharma, D. and Davidson, N. E. (2003) A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2’-deoxycytidine. Breast Cancer Res. Treat. 81, 177–186.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou, Q., Atadja, P. and Davidson, N. E. (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol. Ther. 6, 64–69.PubMedCrossRefGoogle Scholar
  20. 20.
    Yang, X., Ferguson, A. T., Nass, S. J., Phillips, D. L., Butash, K. A., Wang, S. M., Herman, J. G. and Davidson, N. E. (2000) Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. Cancer Res. 60, 6890–6894.PubMedGoogle Scholar
  21. 21.
    Sharma, D., Saxena, N. K., Davidson, N. E. and Vertino, P. M. (2006) Restoration of tamoxifen sensitivity in estrogen receptor-negative breast cancer cells: tamoxifen-bound reactivated ER recruits distinctive corepressor complexes. Cancer Res. 66, 6370–6378.PubMedCrossRefGoogle Scholar
  22. 22.
    Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S. H., Watkins, D. N., Herman, J. G. and Baylin, S. B. (2006) Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40.PubMedCrossRefGoogle Scholar
  23. 23.
    Jung, J. W., Lee, S., Seo, M. S., Park, S. B., Kurtz, A., Kang, S. K. and Kang, K. S. (2010) Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol. Life Sci. 67, 1165–1176.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou, Q., Chaerkady, R., Shaw, P. G., Kensler, T. W., Pandey, A. and Davidson, N. E. (2010) Screening for therapeutic targets of vorinostat by SILAC-based proteomic analysis in human breast cancer cells. Proteomics 10, 1029–1039.PubMedGoogle Scholar
  25. 25.
    Kim, S. C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., Grishin, N. V., White, M., Yang, X. J. and Zhao, Y. (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell. 23, 607–618.PubMedCrossRefGoogle Scholar
  26. 26.
    Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V. and Mann, M. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840.PubMedCrossRefGoogle Scholar
  27. 27.
    Gnad, F., Ren, S., Choudhary, C., Cox, J. and Mann, M. (2010) Predicting Posttranslational Lysine Acetylation Using Support Vector Machines. Bioinformatics 26,1666–1668.PubMedCrossRefGoogle Scholar
  28. 28.
    Beck, H. C. Mass spectrometry in epigenetic research. Methods Mol Biol. 593, 263–282Google Scholar
  29. 29.
    Yoshida, M., Kijima, M., Akita, M. and Beppu, T. (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174–17179.PubMedGoogle Scholar
  30. 30.
    Cousens, L. S., Gallwitz, D. and Alberts, B. M. (1979) Different accessibilities in chromatin to histone acetylase. J. Biol. Chem. 254, 1716–1723.PubMedGoogle Scholar
  31. 31.
    Jackson, V., Shires, A., Chalkley, R. and Granner, D. K. (1975) Studies on highly metabolically active acetylation and phosphorylation of histones. J. Biol. Chem. 250, 4856–4863.PubMedGoogle Scholar
  32. 32.
    Rodriguez-Collazo, P., Leuba, S. H. and Zlatanova, J. (2009) Robust methods for purification of histones from cultured mammalian cells with the preservation of their native modifications. Nucleic Acids Res. 37, e81PubMedCrossRefGoogle Scholar
  33. 33.
    Young, N. L., DiMaggio, P. A., Plazas-Mayorca, M. D., Baliban, R. C., Floudas, C. A. and Garcia, B. A. (2009) High throughput characterization of combinatorial histone codes. Mol. Cell. Proteomics. 8, 2266–2284.PubMedCrossRefGoogle Scholar
  34. 34.
    Tong, Y. and Falk, J. (2009) Genome-wide analysis for protein-DNA interaction: ChIP-chip. Methods Mol Biol. 590, 235–251.PubMedCrossRefGoogle Scholar
  35. 35.
    Reimer, J. J. and Turck, F. (2010) Genome-wide mapping of protein-DNA interaction by chromatin immunoprecipitation and DNA microarray hybridization (ChIP-chip). Part A: ChIP-chip molecular methods. Methods Mol Biol. 631, 139–160.PubMedCrossRefGoogle Scholar
  36. 36.
    Gobel, U., Reimer, J. and Turck, F. (2010) Genome-wide mapping of protein-DNA interaction by chromatin immunoprecipitation and DNA microarray hybridization (ChIP-chip). Part B: ChIP-chip data analysis. Methods Mol. Biol. 631, 161–184.PubMedCrossRefGoogle Scholar
  37. 37.
    Keen, J. C., Garrett-Mayer, E., Pettit, C., Mack, K. M., Manning, J., Herman, J. G. and Davidson, N. E. (2004) Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1) and estrogen receptor alpha (ER) expression in human breast cancer cells. Cancer Biol. Ther. 3, 1304–1312.PubMedCrossRefGoogle Scholar
  38. 38.
    Weinmann, A. S. and Farnham, P. J. (2002) Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Methods 26, 37–47.PubMedCrossRefGoogle Scholar
  39. 39.
    Huang, Y., Greene, E., Murray Stewart, T., Goodwin, A. C., Baylin, S. B., Woster, P. M. and Casero, R. A., Jr. (2007) Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc. Natl. Acad. Sci. U. S. A. 104, 8023–8028.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yi Huang
    • 1
  • Patrick G. Shaw
    • 1
  • Nancy E. Davidson
    • 1
  1. 1.University of Pittsburgh Cancer InstitutePittsburghUSA

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