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Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

Key Points

  • Alteration of chromatin architecture by means of post-translational modifications of histone tails is an important process for the regulation of gene expression. The coordinated actions of histone-tail acetylation, methylation and phosphorylation, and ATP-dependent chromatin remodelling, allow fine control of gene activation or repression.

  • Histone acetylation and deacetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylatransferases (HDACs).

  • In cancer, the molecular processes that lead to inappropriate expression of genes due to altered chromatin structure are now being identified, and aberrant acetylation of histone tails is strongly linked to carcinogenesis. So, targeting the transcriptional lesions that lead to neoplasia provides an opportunity for therapeutic intervention at the very apex of the transformation process. Such therapies could affect several molecular programmes, and would therefore be more powerful than targeting the end stages of a single disrupted molecular pathway.

  • HDAC inhibitors are an exciting new class of chemotherapeutic drugs. These agents interact with the catalytic site of HDACs, block substrate access and allow hyperacetylation of histone tails.

  • The anticancer potential of HDAC inhibitors stems from their ability to affect several cellular processes that are dysregulated in neoplastic cells. Principally, activation of differentiation programmes, inhibition of the cell cycle and induction of apoptosis are the key antitumour activities of HDAC inhibitors. In addition, activation of the host immune response and inhibition of angiogenesis might also have important roles in HDAC-inhibitor-mediated tumour regression in vivo.

  • Much interest and excitement has been generated following the success of HDAC inhibitors in potently inhibiting tumour progression in rodent models. HDAC inhibitors can mediate histone acetylation in vivo, induce tumour-cell differentiation or apoptosis depending on the cell type, and are associated with minimal toxicity as assessed by weight loss and post-mortem analyses.

  • Given the success of HDAC inhibitors in preclinical studies, Phase I and II clinical trials using several different inhibitors have now been initiated. These drugs seem to be well tolerated at the doses required to hyperacetylate histones and achieve clinical outcomes, and their use in combination therapies is an area that can be further exploited in the clinic.

Abstract

The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer.

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Figure 1: Chromatin structure regulates transcriptional activity.
Figure 2: Regulation of cell growth and survival by HDAC inhibitors.
Figure 3: Induction of cell death by HDAC inhibitors.

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References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).An excellent review, which outlines the molecular defects that must occur for the transformation of a normal cell into a tumour cell.

    Article  CAS  PubMed  Google Scholar 

  2. Jacobson, S. & Pillus, L. Modifying chromatin and concepts of cancer. Curr. Opin. Genet. Dev. 9, 175–184 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Wu, J. & Grunstein, M. 25 Years after the nucleosome model: chromatin modifications. Trends Biochem. Sci. 25, 619–623 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).The nucleosome crystal structure was solved in this study.

    Article  CAS  PubMed  Google Scholar 

  5. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Flaus, A. & Owen-Hughes, T. Mechanisms for ATP-dependent chromatin remodelling. Curr. Opin. Genet. Dev. 11, 148–154 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Marmorstein, R. & Roth, S. Y. Histone acetyltransferases: function, structure, and catalysis. Curr. Opin. Genet. Dev. 11, 155–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Sterner, D. E. & Berger, S. L. Acetylation of histones and transcription-related factors. Microbiol. Mol. Biol. Rev. 64, 435–459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gray, S. G. & Ekstrom, T. J. The human histone deacetylase family. Exp. Cell Res. 262, 75–83 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Khochbin, S., Verdel, A., Lemercier, C. & Seigneurin-Berny, D. Functional significance of histone deacetylase diversity. Curr. Opin. Genet Dev. 11, 162–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Fischle, W., Kiermer, V., Dequiedt, F. & Verdin, E. The emerging role of class II histone deacetylases. Biochem. Cell Biol. 79, 337–348 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, H. J., Chun, M. & Kandror, K. V. Tip60 and HDAC7 interact with the endothelin receptor A and may be involved in downstream signaling. J. Biol. Chem. 276, 16597–16600 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Vaziri, H. et al. hSIR2(SIRT1) Functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Robertson, K. D. DNA methylation, methyltransferases, and cancer. Oncogene 20, 3139–3155 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Esteller, M. & Herman, J. G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 196, 1–7 (2002)

    Article  CAS  PubMed  Google Scholar 

  18. Kouzarides, T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9, 40–48 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Muller, C. & Leutz, A. Chromatin remodeling in development and differentiation. Curr. Opin. Genet. Dev. 11, 167–174 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Muraoka, M. et al. p300 Gene alterations in colorectal and gastric carcinomas. Oncogene 12, 1565–1569 (1996).

    CAS  PubMed  Google Scholar 

  21. Giles, R. H., Peters, D. J. & Breuning, M. H. Conjunction dysfunction: CBP/p300 in human disease. Trends Genet. 14, 178–183 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nature Genet. 24, 300–303 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000).

    CAS  PubMed  Google Scholar 

  24. Grossman, S. R. p300/CBP/p53 Interaction and regulation of the p53 response. Eur. J. Biochem. 268, 2773–2778 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Liang, J., Prouty, L., Williams, B. J., Dayton, M. A. & Blanchard, K. L. Acute mixed lineage leukemia with an inv(8)(p11q13) resulting in fusion of the genes for MOZ and TIF2. Blood 92, 2118–2122 (1998).

    CAS  PubMed  Google Scholar 

  26. Panagopoulos, I. et al. Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13). Hum. Mol. Genet. 10, 395–404 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Lin, R. J., Sternsdorf, T., Tini, M. & Evans, R. M. Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20, 7204–7215 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Zelent, A., Guidez, F., Melnick, A., Waxman, S. & Licht, J. D. Translocations of the RARα gene in acute promyelocytic leukemia. Oncogene 20, 7186–7203 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Pandolfi, P. P. Transcription therapy for cancer. Oncogene 20, 3116–3127 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Heibert, S. W. et al. Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins. Cancer Chemother. Pharmacol. 48, S31–S34 (2001).

  31. Licht, J. D. AML1 and the AML1–ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 20, 5660–5679 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Huynh, K. D., Fischle, W., Verdin, E. & Bardwell, V. J. BCoR, A novel corepressor involved in BCL-6 repression. Genes Dev. 14, 1810–1823 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. McKinsey, T. A., Zhang, C. L. & Olson, E. N. Control of muscle development by dueling HATs and HDACs. Curr. Opin. Genet. Dev. 11, 497–504 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Soengas, M. S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Teitz, T. et al. Caspase -8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nature Med. 6, 529–535 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Rountree, M. R., Bachman, K. E., Herman, J. G. & Baylin, S. B. DNA methylation, chromatin inheritance, and cancer. Oncogene 20, 3156–3165 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Dervan, P. B. & Burli, R. W. Sequence-specific DNA recognition by polyamides. Curr. Opin. Chem. Biol. 3, 688–693 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Mapp, A. K., Ansari, A. Z., Ptashne, M. & Dervan, P. B. Activation of gene expression by small molecule transcription factors. Proc. Natl Acad. Sci. USA 97, 3930–3935 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Liu, P. Q. et al. Regulation of an endogenous locus using a panel of designed zinc finger proteins targeted to accessible chromatin regions. Activation of vascular endothelial growth factor A. J. Biol Chem. 276, 11323–11334 (2001).References 38 and 39 describe the production of functional designer transcription factors using polymides and zinc-finger proteins.

    Article  CAS  PubMed  Google Scholar 

  40. Finnin, M. S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).This group solved the structure of an HDAC inhibitor bound to an HDAC.

    Article  CAS  PubMed  Google Scholar 

  41. Marks, P. A., Richon, V. M., Breslow, R. & Rifkind, R. A. Histone deacetylase inhibitors as new cancer drugs. Curr. Opin. Oncol. 13, 477–483 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Weidle, U. H. & Grossmann, A. Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment. Anticancer Res. 20, 1471–1485 (2000).

    CAS  PubMed  Google Scholar 

  43. Phiel, C. J. et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276, 36734–36741 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Gottlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).References 43 and 44 describe the characterization of the antiepileptic drug valproic acid as an HDAC inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Komatsu, Y. et al. Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res. 61, 4459–4466 (2001).

    CAS  PubMed  Google Scholar 

  46. Furumai, R. et al. Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc. Natl Acad. Sci. USA 98, 87–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Mariadason, J. M., Corner, G. A. & Augenlicht, L. H. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res. 60, 4561–4572 (2000).The use of DNA microarrays to identify genes that are regulated by HDAC inhibitors.

    CAS  PubMed  Google Scholar 

  48. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103–107 (1999).This study shows the functional synergy between HDAC inhibitors and the DNA demethylating agent 5-azadC.

    Article  CAS  PubMed  Google Scholar 

  50. Marks, P. A., Richon, V. M. & Rifkind, R. A. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl Cancer Inst. 92, 1210–1216 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Marks, P. A. et al. Histone deacetylases and cancer: causes and therapies. Nature Rev. Cancer 1, 194–202 (2001)

    Article  CAS  Google Scholar 

  52. Kramer, O. H., Gottlicher, M. & Heinzel, T. Histone deacetylase as a therapeutic target. Trends Endocrinol. Metab. 12, 294–300 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Qiu, L. et al. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol. Biol Cell. 11, 2069–2083 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ruefli, A. A. et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of BID and production of reactive oxygen species. Proc. Natl Acad. Sci. USA 98, 10833–10838 (2001).The identification of a new mechanism of activation of the intrinsic apoptotic pathway by SAHA.

    Article  CAS  PubMed  Google Scholar 

  55. He, L. Z. et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J. Clin. Invest. 108, 1321–1330 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ferrara, F. F. et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. 61, 2–7 (2001).

    PubMed  Google Scholar 

  57. Kosugi, H. et al. Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia 13, 1316–1324 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Lipinski, M. M. & Jacks, T. The retinoblastoma gene family in differentiation and development. Oncogene 18, 7873–7882 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Sandor, V. et al. p21-Dependent G1 arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br. J. Cancer 83, 817–825 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rosato, R. R., Wang, Z., Gopalkrishnan, R. V., Fisher, P. B. & Grant, S. Evidence of a functional role for the cyclin-dependent-kinase inhibitor p21WAF1/CIP1/MDA6 in promoting differentiation and preventing mitochondrial dysfunction and apoptosis induced by sodium butyrate in human myelomonocytic leukemia cells (U937). Int. J. Oncol. 19, 181–191 (2001).

    CAS  PubMed  Google Scholar 

  61. Burgess, A. J. et al. Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity. Mol. Pharmacol. 60, 828–837 (2001).

    CAS  PubMed  Google Scholar 

  62. Vrana, J. A. et al. Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by BCL-2/BCL-XL, c-JUN, and p21CIP1, but independent of p53. Oncogene 18, 7016–7025 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Zhu, L. & Skoultchi, A. I. Coordinating cell proliferation and differentiation. Curr. Opin. Genet. Dev. 11, 91–97 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Munster, P. N. et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res. 61, 8492–8497 (2001).

    CAS  PubMed  Google Scholar 

  65. Kwon, S. H. et al. Apicidin, a histone deacetylase inhibitor, induces apoptosis and FAS/FAS ligand expression in human acute promyelocytic leukemia cells. J. Biol. Chem. 6, 6 (2001)

    Google Scholar 

  66. Glick, R. D. et al. Hybrid polar histone deacetylase inhibitor induces apoptosis and CD95/CD95 ligand expression in human neuroblastoma. Cancer Res. 59, 4392–4399 (1999).References 65 and 66 outline the potential role of the death-receptor pathway in apoptosis that is induced by HDAC inhibitors.

    CAS  PubMed  Google Scholar 

  67. Mello, J. A. & Almouzni, G. The ins and outs of nucleosome assembly. Curr. Opin. Genet. Dev. 11, 136–141 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Green, D. R. Apoptotic pathways: paper wraps stone blunts scissors. Cell 102, 1–4 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Bonnotte, B. et al. Cancer cell sensitization to Fas-mediated apoptosis by sodium butyrate. Cell Death Differ. 5, 480–487 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Bernhard, D. et al. Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death Differ. 8, 1014–1021 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Wang, R., Brunner, T., Zhang, L. & Shi, Y. Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression. Oncogene 17, 1503–1508 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Bernhard, D. et al. Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. FASEB J. 13, 1991–2001 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Suzuki, T. et al. Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines. Int. J. Cancer 88, 992–997 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Cao, X. X., Mohuiddin, I., Ece, F., McConkey, D. J. & Smythe, W. R. Histone deacetylase inhibitor downregulation of Bcl-XL gene expression leads to apoptotic cell death in mesothelioma. Am. J. Respir. Cell. Mol. Biol. 25, 562–568 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Zhu, W. G., Lakshmanan, R. R., Beal, M. D. & Otterson, G. A. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res. 61, 1327–1333 (2001).

    CAS  PubMed  Google Scholar 

  76. Weiser, T. S. et al. Sequential 5-aza-2′-deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY–ESO1. J. Immunother. 24, 151–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Amin, H. M., Saeed, S. & Alkan, S. Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of DAXX in acute promyelocytic leukaemia with t(15;17). Br. J. Haematol. 115, 287–297 (2001)

    Article  CAS  PubMed  Google Scholar 

  78. Trapani, J. A. et al. Perforin-dependent nuclear entry of granzyme B precedes apoptosis, and is not a consequence of nuclear membrane dysfunction. Cell Death Differ. 5, 488–496 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Maeda, T., Towatari, M., Kosugi, H. & Saito, H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 96, 3847–3856 (2000).

    CAS  PubMed  Google Scholar 

  80. Magner, W. J. et al. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J. Immunol. 165, 7017–7024 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Mishra, N., Brown, D. R., Olorenshaw, I. M. & Kammer, G. M. Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-γ gene and protein expression in lupus T cells. Proc. Natl Acad. Sci. USA 98, 2628–2633 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Shestakova. E., Bandu, M. T., Doly, J. & Bonnefoy, E. Inhibition of histone deacetylation induces constitutive derepression of the beta interferon promoter and confers antiviral activity. J. Virol. 75, 3444–3452 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, M. S. et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nature Med. 7, 437–443 (2001).This study shows that the antitumour activity of HDAC inhibitors is mediated by the inhibition of angiogenesis.

    Article  PubMed  Google Scholar 

  84. Sternson, S. M., Wong, J. C., Grozinger, C. M. & Schreiber, S. L. Synthesis of 7,200 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 

  85. Meinke, P. T. & Liberator, P. Histone deacetylase: a target for antiproliferative and antiprotozoal agents. Curr. Med. Chem. 8, 211–235 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Jung, M. Inhibitors of histone deacetylase as new anticancer agents. Curr. Med. Chem. 8, 1505–1511 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Remiszewski, S. W. et al. Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates. J. Med. Chem. 45, 753–757 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Richon, V. M. et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc. Natl Acad. Sci. USA 95, 3003–3007 (1998).The characterization of the production and function of a new class of HDAC inhibitor.

    Article  CAS  PubMed  Google Scholar 

  89. Butler, L. M. et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 60, 5165–5170 (2000).

    CAS  PubMed  Google Scholar 

  90. Reed, J. C. Dysregulation of apoptosis in cancer. J. Clin. Oncol. 17, 2941–2953 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Takakura, M. et al. Telomerase activation by histone deacetylase inhibitor in normal cells. Nucleic Acids Res. 29, 3006–3011 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cress, W. D. & Seto, E. Histone deacetylases, transcriptional control, and cancer. J. Cell. Physiol. 184, 1–16 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Terao, Y. et al. Sodium butyrate induces growth arrest and senescence-like phenotypes in gynecologic cancer cells. Int. J. Cancer 94, 257–267 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Vigushin, D. M. et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin. Cancer Res. 7, 971–976 (2001).

    CAS  PubMed  Google Scholar 

  95. Coffey, D. C. et al. The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. Cancer Res. 61, 3591–3594 (2001).

    CAS  PubMed  Google Scholar 

  96. Ueda, H. et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968.III. Antitumor activities on experimental tumors in mice. J. Antibiot. (Tokyo) 47, 315–323 (1994).

    Article  CAS  Google Scholar 

  97. Saito, A. et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc. Natl Acad. Sci. USA 96, 4592–4597 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Kosugi, H. et al. In vivo effects of a histone deacetylase inhibitor, FK228, on human acute promyelocytic leukemia in NOD/SHI–SCID/SCID mice. Jpn J. Cancer Res. 92, 529–536 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gilbert, J. et al. A Phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin. Cancer Res. 7, 2292–2300 (2001).

    CAS  PubMed  Google Scholar 

  100. Carducci, M. A. et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-hr infusion schedule. Clin. Cancer Res. 7, 3047–3055 (2001).

    CAS  PubMed  Google Scholar 

  101. Warrell, R. P. Jr, He, L. Z., Richon, V., Calleja, E. & Pandolfi, P. P. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl Cancer Inst. 90, 1621–1625 (1998).This paper shows the use of HDAC inhibitors for the treatment of APL.

    Article  CAS  PubMed  Google Scholar 

  102. Piekarz, R. L. et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 98, 2865–2868 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Ruefli, A. A. Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-gp expressing cells. Int. J. Cancer. (in the press).

  104. Greenberg, V. L., Williams, J. M., Cogswell, J. P., Mendenhall, M. & Zimmer, S. G. Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. Thyroid 11, 315–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Harbour, J. W. & Dean, D. C. Chromatin remodeling and Rb activity. Curr. Opin. Cell Biol. 12, 685–689 (2000).An excellent review, which outlines the importance of HDACs for transcriptional repression by RB.

    Article  CAS  PubMed  Google Scholar 

  106. Puri, P. L. et al. Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. Mol. Cell 8, 885–897 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Kihara-Negishi, F. et al. In vivo complex formation of PU.1 with HDAC1 associated with PU.1-mediated transcriptional repression. Oncogene 20, 6039–6047 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Ashburner, B. P., Westerheide, S. D. & Baldwin, A. S. Jr. The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell. Biol. 21, 7065–7077 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fuks, F., Burgers, W. A., Godin, N., Kasai, M. & Kouzarides, T. DNMT3A binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 20, 2536–2544 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chen, L., Fischle, W., Verdin, E. & Greene, W. C. Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293, 1653–1657 (2001).

    Article  CAS  Google Scholar 

  111. Rountree, M. R., Bachman, K. E. & Baylin, S. B. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature Genet. 25, 269–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Yarden, R. I. & Brody, L. C. BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl Acad. Sci. USA 96, 4983–4988 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Doetzlhofer, A. et al. Histone deacetylase 1 can repress transcription by binding to Sp1. Mol. Cell. Biol. 19, 5504–5511 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ng, H. H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58–61 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Coull, J. J. et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J. Virol. 74, 6790–6799 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Robertson, K. D. et al. DNMT1 forms a complex with RB, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature Genet. 25, 338–342 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Luo, J., Su, F., Chen, D., Shiloh, A. & Gu, W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408, 377–381 (2000).An outline of the regulation of p53 function by factor acetyltransferase activity.

    Article  CAS  PubMed  Google Scholar 

  118. Kim, G. D. et al. Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J. Biol. Chem. 274, 31127–31130 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I apologise to those whose work was not cited or discussed due to space limitations. I thank S. Russell, A. Ruefli and members of my laboratory for helpful discussions, and E. Baker for help with Figure 1. R.W.J. is a Wellcome Trust Senior Research Fellow and is supported by the National Health and Medical Research Council of Australia.

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DATABASES

Cancer.gov

breast cancer

cervical carcinoma

colorectal cancer

endometrial carcinoma

gastric carcinoma

leukaemia

lung cancer

lymphoma

multiple myeloma

myelodysplastic syndrome

non Hodgkin's lymphoma

oral carcinoma

ovarian carcinoma

pancreatic carcinoma

prostate carcinoma

skin cancer

stomach cancer

LocusLink

ACTR

AIF

AML

androgen receptor

APAF1

APC

ATF2

ATM

BAK

BAX

BCL2

BCL6

BCLX L

BID

BMYB

BRCA1

E-cadherin

caspase-3

caspase-7

caspase-8

caspase-9

caspase-10

β-catenin

CBP

CD40

CD80

CD86

CD95

CD95L

CDK2

CDKN1A

CDKN1B

CDKN2A

CDKN2B

CPA3

cyclin A

cyclin D

cyclin E

cytochrome c

DAPK

DHFR

DNMT1

DNMT3A

DNMT3B

E2F

EKLF

endothelin A receptor

endothelin B receptor

ER

ETO

FADD

GATA1

GATA2

GCN5

gelsolin

GM-CSF

GSTP1

H1

H2A

H2B

H3

H4

HAT1

HBO1

HDAC1

HDAC2

HDAC3

HDAC4

HDAC5

HDAC6

HDAC7

HDAC8

HDAC9

HDAC10

HIF1A

HMG1

HMG14

HMG17

HMGIY

HSP86

HTRA2

ICAM1

IFNB

IFNG

IGFBP3

IL2

IL8

IL10

IRF1

IRF2

LKB1

MAD

MAGE3

MAX

MBD1

MBD2

MBD3

MECP2

MEF2

MGMT

MLH1

MLL

MORF

MOZ

c-MYB

MYC

MYOD

NCOR

NES1

NF-κB

NPM

p53

P107

p300

PAI2

PARP

PCAF

PKCD

PLZF

PML

PU.1

RB

RARα

RARB

RIZ1

RXR

SIRT1

SIRT2

SIRT3

SIRT4

SIRT5

SIRT6

SIRT7

SMAC

SMRT

SOCS1

SRC1

STAT5b

TAFII250

TEL

TERT

TFIID

TFIIE

TFIIF

TGFB1

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thrombospondin 1

TIF2

TIMP3

TIP60

TMS1

TNF receptor

TP73

TRAIL receptor

VEGF

VHL

YY1

Medscape DrugInfo

valproic acid

OMIM

acute lymphoblastic leukaemia

acute myelogenous leukaemia

acute promyelocytic leukaemia

Rubinstein–Taybi syndrome

<i>Saccharomyces</i> Genome Database

Gcn5

Sir2

FURTHER INFORMATION

Boston University School of Medicine

Cancer.gov

Chromatin Network

Greenebaum Cancer Center

Johns Hopkins Oncology Center

Memorial Sloan–Kettering Cancer Center

Mount Sinai Hospital

National Cancer Institute

Ohio State University

Regulation of Gene Expression

Glossary

APOPTOSIS

Also termed 'programmed cell death', is a natural physiological process that occurs during disease and development, and is initiated by cells in response to environmental stresses. It is characterized morphologically by membrane blebbing, chromatin condensation, loss of cell volume and DNA fragmentation, and biochemically by caspase activation.

ONCOGENE

A normal gene that stimulates appropriate cell growth under normal conditions. When mutated or overexpressed, it can induce the uncontrolled proliferation of cells in the absence of growth signals and mediate neoplastic transformation.

TUMOUR-SUPPRESSOR GENE

A gene that inhibits cell-cycle progression or induces apoptosis to regulate cell numbers. Often mutated or functionally inactivated in cancer.

EPIGENETIC

A change that influences phenotype without altering genotype.

DIFFERENTIATION

The structural and functional specialization of cells and tissues during development. It occurs by the gradual maturation of cells with specialized structures and functions from unspecialized precursors as a result of changes in gene expression.

CELL CYCLE

The sequence of stages — mitosis (M), gap 1 (G1), the DNA-synthesis stage (S) and gap 2 (G2) — that an actively growing cell passes through between the time it is formed and the time it divides to give two new cells. During this time, it doubles its cytoplasmic constituents, replicates its DNA and finally divides to give two daughter cells.

ANGIOGENESIS

The growth of new blood vessels from pre-existing ones. A complex phenomenon that is required for the continued growth and survival of solid neoplasms.

CHROMATIN REMODELLING

An alteration in chromatin structure that affects the nuclease sensitivity of a region of chromatin. Accomplished by covalent modification of histones and/or the action of ATP-dependent remodelling complexes.

CHEMOTHERAPY

Initially defined by Paul Ehrlich as “the use of a drug to combat an invading parasite without damaging the host”. Now commonly refers to the treatment of cancer using drugs that are selectively toxic for the cancerous cells.

CHROMOSOMAL TRANSLOCATION

A genetic rearrangement in which part of a chromosome is detached and transferred to another chromosome, or to another portion of the same chromosome. Reciprocal translocation is when two chromosomes exchange DNA.

LEUKAEMIA

A chronic or acute haematopoietic cancer that is characterized by unrestrained growth and loss of differentiation of leukocytes and their precursors. Leukaemia is classified according to the dominant cell type and severity of the disease.

ZINC FINGER

A protein domain that contains two invariant cysteine, and two invariant histidine, residues that bind a single zinc atom. These domains often confer the DNA-binding component of transcription factors, but can mediate protein–protein interactions.

PHARMACOKINETICS

The study of the metabolism and action of drugs, with particular emphasis on the time that is required for absorption, duration of action, distribution in the body and method of excretion.

BIOAVAILABILITY

The rate and extent to which an active drug enters the general circulation, thereby permitting access to the site of action. Determined by measuring the concentration of the drug in body fluids, or by the magnitude of the pharmacological response.

DIFFERENTIAL DISPLAY

A method for identifying differentially expressed genes using anchored oligo-dT and random oligonucleotide primers and polymerase chain reaction (PCR) on reverse-transcribed RNA from different cell populations. The amplified complementary DNAs are displayed, and comparisons are drawn between the different cell populations.

DNA MICROARRAY

A high-throughput, differential gene-expression screen of complementary DNA or oligonucleotide libraries that are printed in extremely high density on microchips. These microchips are probed with a mixture of fluorescently tagged cDNAs that are produced from two different cell populations, and analysed with a laser confocal scanner.

CHECKPOINT

A point at which the cell cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

KINETOCHORE

A structural feature of the chromosome to which microtubules of the mitotic spindle attach.

CASPASES

A family of cysteine proteases that cleave various cellular substrates, which leads to the morphological changes that are associated with apoptosis. Might also activate inflammatory cytokines such as interleukin-1.

TELOMERASE

An RNA-containing enzyme complex that extends chromosome ends (telomeres) by copying its RNA sequence repeatedly into chromosomal DNA.

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Johnstone, R. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1, 287–299 (2002). https://doi.org/10.1038/nrd772

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