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.
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References
Feinberg, A. P. and Tycko, B. (2004) The history of cancer epigenetics. Nat Rev Cancer. 4, 143–153.
Jones, P. A. and Baylin, S. B. (2007) The epigenomics of cancer. Cell 128, 683–692.
Jenuwein, T. and Allis, C. D. (2001) Translating the histone code. Science 293, 1074–1080.
Ho, L. and Crabtree, G. R. (2010) Chromatin remodelling during development. Nature 463, 474–484.
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.
Marson, C. M. (2009) Histone deacetylase inhibitors: design, structure-activity relationships and therapeutic implications for cancer. Anticancer Agents Med Chem. 9, 661–692.
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.
Marks, P. A., Richon, V. M., Miller, T. and Kelly, W. K. (2004) Histone deacetylase inhibitors. Adv.Cancer. Res. 91, 137–168.
Ficner, R. (2009) Novel structural insights into class I and II histone deacetylases. Curr Top. Med. Chem. 9, 235–240.
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.
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.
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.
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.
Marks, P. A. and Xu, W. S. (2009) Histone deacetylase inhibitors: Potential in cancer therapy. J. Cell. Biochem. 107, 600–608.
Campas-Moya, C. (2009) Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc) 45, 787–795.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gnad, F., Ren, S., Choudhary, C., Cox, J. and Mann, M. (2010) Predicting Posttranslational Lysine Acetylation Using Support Vector Machines. Bioinformatics 26,1666–1668.
Beck, H. C. Mass spectrometry in epigenetic research. Methods Mol Biol. 593, 263–282
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.
Cousens, L. S., Gallwitz, D. and Alberts, B. M. (1979) Different accessibilities in chromatin to histone acetylase. J. Biol. Chem. 254, 1716–1723.
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.
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, e81
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.
Tong, Y. and Falk, J. (2009) Genome-wide analysis for protein-DNA interaction: ChIP-chip. Methods Mol Biol. 590, 235–251.
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.
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.
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.
Weinmann, A. S. and Farnham, P. J. (2002) Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Methods 26, 37–47.
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.
Acknowledgments
This work was funded by NIH SPORE grant CA88843 (to N.E.D.) and the Breast Cancer Research Foundation (to N.E.D.).
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Huang, Y., Shaw, P.G., Davidson, N.E. (2011). Inhibition of Histone Deacetylases. In: Tollefsbol, T. (eds) Epigenetics Protocols. Methods in Molecular Biology, vol 791. Humana Press. https://doi.org/10.1007/978-1-61779-316-5_22
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DOI: https://doi.org/10.1007/978-1-61779-316-5_22
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