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Anticancer activities of histone deacetylase inhibitors

Key Points

  • Histone deacetylase inhibitors are novel anticancer agents that induce tumour cell death, differentiation, and/or cell cycle arrest. As well as their intrinsic effects on tumour cells, histone deacetylase inhibitors may additionally affect neoplastic growth and survival by regulating host immune responses and tumour vasculature.

  • The pleiotropic cellular effects of HDACi can act cooperatively to mediate potent anti-tumour activities; however, the molecular processes underlying these effects of HDACi remain to be fully elucidated.

  • The activity of diverse non-histone proteins can be regulated by acetylation indicating that HDACi may have a much broader effect on cellular physiology than originally understood. Altered gene expression through the effects of HDACi on the activity of transcription factors and transcription-independent effects of HDACi are also important in their anticancer activities.

  • In preclinical studies, several classes of HDACi have been found to have potent anticancer activities, and some have demonstrated promising therapeutic potential in early clinical trials for haematological malignancies such as cutaneous T-cell lymphoma, myelodysplastic syndromes and diffuse B-cell lymphoma.

  • While HDACi show promise as single agent anticancer drugs, their use in combination with other agents may prove to be their most useful application. Already, HDACi have been shown to function synergistically with a host of structurally and functionally diverse chemical compounds and biologically active polypeptides.

Abstract

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.

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Figure 1: Histone deacetylase inhibitors lower the apoptotic threshold of tumour cells.
Figure 2: Effects of histone deacetylase inhibition on non-histone proteins.

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References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70. (2000).

    CAS  PubMed  Google Scholar 

  2. Kinzler, K. W. & Vogelstein, B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 386, 761–763 (1997).

    CAS  PubMed  Google Scholar 

  3. Lund, A. H. & van Lohuizen, M. Epigenetics and cancer. Genes Dev. 18, 2315–2335 (2004). This manuscript highlights key aspects of epigenetic gene regulation and discusses known connections between epigenetic gene (de)regulation and cancer.

    CAS  PubMed  Google Scholar 

  4. Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer- a mechanism for early oncogenic pathway addiction? Nature Rev. Cancer 6, 107–116 (2006).

    CAS  Google Scholar 

  5. Nightingale, K. P., O'Neill, L. P. & Turner, B. M. Histone modifications: signalling receptors and potential elements of a heritable epigenetic code. Curr. Opin. Genet. Dev. 16, 125–136 (2006).

    CAS  PubMed  Google Scholar 

  6. Roth, S. Y., Denu, J. M. & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81–120 (2001).

    CAS  PubMed  Google Scholar 

  7. Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).

    CAS  PubMed  Google Scholar 

  8. Pandolfi, P. P. Histone deacetylases and transcriptional therapy with their inhibitors. Cancer Chemother. Pharmacol. 48 (Suppl. 1), S17–S19 (2001).

    CAS  PubMed  Google Scholar 

  9. Marks, P. A. & Jiang, X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle 4, 549–551 (2005).

    CAS  PubMed  Google Scholar 

  10. Lindemann, R. K., Gabrielli, B. & Johnstone, R. W. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle 3, 779–788 (2004).

    CAS  PubMed  Google Scholar 

  11. Jabbour, E. J. & Giles, F. J. New agents in myelodysplastic syndromes. Curr. Hematol. Rep. 4, 191–199 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Cote, S. et al. Response to histone deacetylase inhibition of novel PML/RARα mutants detected in retinoic acid-resistant APL cells. Blood 100, 2586–2596 (2002).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    CAS  PubMed  Google Scholar 

  16. 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). References 12–16 outline the molecular rationale for combining HDACi and retinoids.

    PubMed  Google Scholar 

  17. Pasqualucci, L. et al. Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6. Leuk. Lymphoma 44 (Suppl. 3), S5–S12 (2003).

    CAS  PubMed  Google Scholar 

  18. Halkidou, K. et al. Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59, 177–189 (2004).

    CAS  PubMed  Google Scholar 

  19. Choi, J. H. et al. Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn J. Cancer Res. 92, 1300–1304 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Wilson, A. J. et al. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J. Biol. Chem. 281, 13548–13558 (2006).

    CAS  PubMed  Google Scholar 

  21. Zhang, Z. et al. Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast Cancer Res. Treat 94, 11–16 (2005).

    CAS  PubMed  Google Scholar 

  22. Zhu, P. et al. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5, 455–463 (2004).

    CAS  PubMed  Google Scholar 

  23. Huang, B. H. et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ. 12, 395–404 (2005).

    CAS  PubMed  Google Scholar 

  24. Song, J. et al. Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS 113, 264–268 (2005).

    CAS  PubMed  Google Scholar 

  25. Zhang, Z. et al. HDAC6 expression is correlated with better survival in breast cancer. Clin. Cancer Res. 10, 6962–6968 (2004).

    CAS  PubMed  Google Scholar 

  26. Glaser, K. B. et al. Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem. Biophys. Res. Commun. 310, 529–536 (2003).

    CAS  PubMed  Google Scholar 

  27. Insinga, A. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nature Med. 11, 71–76 (2005). Together with reference 181 demonstrated a key tumour selective role for the TRAIL (death receptor) pathway in the induction of apoptosis following treatment with HDAC inhibitors.

    CAS  PubMed  Google Scholar 

  28. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005). This manuscript describes the comprehensive analysis of global histone H4 modifications, and identified modification differences between normal tissues and tumor cells.

    CAS  PubMed  Google Scholar 

  29. Leder, A., Orkin, S. & Leder, P. Differentiation of erythroleukemic cells in the presence of inhibitors of DNA synthesis. Science 190, 893–894 (1975).

    CAS  PubMed  Google Scholar 

  30. Riggs, M. G., Whittaker, R. G., Neumann, J. R. & Ingram, V. M. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462–464 (1977).

    CAS  PubMed  Google Scholar 

  31. Yoshida, M., Kijima, M., Akita, M. & Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174–17179 (1990).

    CAS  PubMed  Google Scholar 

  32. 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). References 29–32 provide a historical time line of the discovery that inhibition of HDAC activity leads to tumour cell differentiation and death.

    CAS  PubMed  Google Scholar 

  33. Fischle, W. et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57 (2002).

    CAS  PubMed  Google Scholar 

  34. Hu, E. et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J. Pharmacol. Exp. Ther. 307, 720–728 (2003).

    CAS  PubMed  Google Scholar 

  35. Li, J. et al. Expression and functional characterization of recombinant human HDAC1 and HDAC3. Life Sci. 74, 2693–2705 (2004).

    CAS  PubMed  Google Scholar 

  36. Furumai, R. et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 62, 4916–4921 (2002).

    CAS  PubMed  Google Scholar 

  37. Qian, D. Z. et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin. Cancer Res. 12, 634–642 (2006).

    CAS  PubMed  Google Scholar 

  38. Warrener, R. et al. Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints. FASEB J. 17, 1550–1552 (2003).

    CAS  PubMed  Google Scholar 

  39. Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M. & Schreiber, S. L. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl Acad. Sci. USA 100, 4389–4394 (2003).

    CAS  PubMed  Google Scholar 

  40. Blagosklonny, M. V. et al. Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol. Cancer Ther. 1, 937–941 (2002).

    CAS  PubMed  Google Scholar 

  41. Drummond, D. C. et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 45, 495–528 (2005).

    CAS  PubMed  Google Scholar 

  42. Dokmanovic, M. & Marks, P. A. Prospects: histone deacetylase inhibitors. J. Cell. Biochem. 96, 293–304 (2005).

    CAS  PubMed  Google Scholar 

  43. Kelly, W. K. & Marks, P. A. Drug insight: Histone deacetylase inhibitors — development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nature Clin. Pract. Oncol. 2, 150–157 (2005). The authors provide an overview of the preclinical development of SAHA (vorinostat), one of the HDACi most advanced in clinical development.

    CAS  Google Scholar 

  44. Kelly, W. K., O'Connor, O. A. & Marks, P. A. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin. Investig. Drugs 11, 1695–1713 (2002).

    CAS  PubMed  Google Scholar 

  45. Johnstone, R. W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Rev. Drug Discov. 1, 287–299 (2002).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  47. Willis, S. N. & Adams, J. M. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17, 617–625 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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). This study identified a new mechanism for activation of the 'intrinsic' apoptotic pathway by SAHA.

    CAS  PubMed  Google Scholar 

  49. Peart, M. J. et al. Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res. 63, 4460–4471 (2003).

    CAS  PubMed  Google Scholar 

  50. Mitsiades, N. et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101, 4055–4062 (2003).

    CAS  PubMed  Google Scholar 

  51. Zhang, Y., Adachi, M., Kawamura, R. & Imai, K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 13, 129–140 (2006).

    CAS  PubMed  Google Scholar 

  52. Zhao, Y. et al. Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc. Natl Acad. Sci. USA 102, 16090–16095 (2005).

    CAS  PubMed  Google Scholar 

  53. Rosato, R. R., Almenara, J. A. & Grant, S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res. 63, 3637–3645 (2003).

    CAS  PubMed  Google Scholar 

  54. Sade, H. & Sarin, A. Reactive oxygen species regulate quiescent T-cell apoptosis via the BH3-only proapoptotic protein BIM. Cell Death Differ. 11, 416–423 (2004).

    CAS  PubMed  Google Scholar 

  55. Marks, P. A., Miller, T. & Richon, V. M. Histone deacetylases. Curr. Opin. Pharmacol. 3, 344–351 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. Gabrielli, B. G., Johnstone, R. W. & Saunders, N. A. Identifying molecular targets mediating the anticancer activity of histone deacetylase inhibitors: a work in progress. Curr Cancer Drug Targets 2, 337–353 (2002).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  Google Scholar 

  60. Richon, V. M., Sandhoff, T. W., Rifkind, R. A. & Marks, P. A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl Acad. Sci. USA 97, 10014–10019 (2000).

    CAS  PubMed  Google Scholar 

  61. Kim, Y. B., Lee, K. H., Sugita, K., Yoshida, M. & Horinouchi, S. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 18, 2461–2470 (1999).

    CAS  PubMed  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sandor, V. et al. P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br. J. Cancer 83, 817–825 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Glaser, K. B. et al. Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol. Cancer Ther. 2, 151–163 (2003).

    CAS  PubMed  Google Scholar 

  65. Chen, Z. et al. Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) α and β messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells. Cancer Lett. 188, 127–140 (2002).

    CAS  PubMed  Google Scholar 

  66. Jaboin, J. et al. MS-27–275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res. 62, 6108–6115 (2002).

    CAS  PubMed  Google Scholar 

  67. 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 

  68. Taddei, A., Roche, D., Bickmore, W. A. & Almouzni, G. The effects of histone deacetylase inhibitors on heterochromatin: implications for anticancer therapy? EMBO Rep. 6, 520–524 (2005). Discusses the consequences of HDAC inhibition (histone hyperacetylation) on heterochromatin structure and dynamics in dividing and non-dividing cells

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Pili, R., Kruszewski, M. P., Hager, B. W., Lantz, J. & Carducci, M. A. Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res. 61, 1477–1485 (2001).

    CAS  PubMed  Google Scholar 

  70. Sasakawa, Y. et al. Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. Biochem. Pharmacol. 66, 897–906 (2003).

    CAS  PubMed  Google Scholar 

  71. Michaelis, M. et al. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol. Pharmacol. 65, 520–527 (2004).

    CAS  PubMed  Google Scholar 

  72. Rossig, L. et al. Inhibitors of histone deacetylation downregulate the expression of endothelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis. Circ. Res. 91, 837–844 (2002).

    PubMed  Google Scholar 

  73. Deroanne, C. F. et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21, 427–436 (2002).

    CAS  PubMed  Google Scholar 

  74. Crazzolara, R. et al. Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia. Br. J. Haematol. 119, 965–969 (2002).

    CAS  PubMed  Google Scholar 

  75. Kim, S. H. et al. Apicidin is a histone deacetylase inhibitor with anti-invasive and anti-angiogenic potentials. Biochem. Biophys. Res. Commun. 315, 964–970 (2004).

    CAS  PubMed  Google Scholar 

  76. Liu, L. T., Chang, H. C., Chiang, L. C. & Hung, W. C. Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res. 63, 3069–3072 (2003).

    CAS  PubMed  Google Scholar 

  77. Klisovic, D. D. et al. Depsipeptide inhibits migration of primary and metastatic uveal melanoma cell lines in vitro: a potential strategy for uveal melanoma. Melanoma Res. 15, 147–153 (2005).

    CAS  PubMed  Google Scholar 

  78. Coradini, D. et al. Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But. Clin. Cancer Res. 10, 4822–4830 (2004).

    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).

    CAS  PubMed  Google Scholar 

  81. Armeanu, S. et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321–6329 (2005).

    CAS  PubMed  Google Scholar 

  82. Skov, S. et al. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res. 65, 11136–11145 (2005). References 81 and 82 demonstrate the induction of the MHC class I-related molecules MIC-A and MIC-B selectively on tumour cells, which renders the cells susceptible to natural killer cell-mediated lysis.

    CAS  PubMed  Google Scholar 

  83. Reddy, P. et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl Acad. Sci. USA 101, 3921–3926 (2004).

    CAS  PubMed  Google Scholar 

  84. Nusinzon, I. & Horvath, C. M. Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc. Natl Acad. Sci. USA 100, 14742–14747 (2003).

    CAS  PubMed  Google Scholar 

  85. Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  87. Johnstone, R. W. & Licht, J. D. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 4, 13–18 (2003).

    CAS  PubMed  Google Scholar 

  88. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    CAS  PubMed  Google Scholar 

  89. Martinez-Balbas, M. A., Bauer, U. M., Nielsen, S. J., Brehm, A. & Kouzarides, T. Regulation of E2F1 activity by acetylation. EMBO J. 19, 662–671 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    CAS  PubMed  Google Scholar 

  91. Pediconi, N. et al. Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nature Cell Biol. 5, 552–558 (2003).

    CAS  PubMed  Google Scholar 

  92. Costanzo, A. et al. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol. Cell 9, 175–186 (2002). References 91 and 92 propose that transcription factor acetylation can occur in response to DNA damage, and that these acetylated factors subsequently favour the transcription of pro-apoptotic genes without affecting the induction of other genes (for example, cell-cycle regulatory genes).

    CAS  PubMed  Google Scholar 

  93. Finzer, P. et al. HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway. Oncogene 23, 4807–4817 (2004).

    CAS  PubMed  Google Scholar 

  94. Hershko, T. & Ginsberg, D. Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J. Biol. Chem. 279, 8627–8634 (2004).

    CAS  PubMed  Google Scholar 

  95. Chipuk, J. E. & Green, D. R. Dissecting p53-dependent apoptosis. Cell Death Differ. 13, 994–1002 (2006).

    CAS  PubMed  Google Scholar 

  96. Tomita, Y. et al. WTp53 but not tumor-derived mutants bind to BCL2 via the DNA binding domain and induce mitochondrial permeabilization. J. Biol. Chem. 281, 8600–8606 (2006).

    CAS  PubMed  Google Scholar 

  97. Xu, Y. Regulation of p53 responses by post-translational modifications. Cell Death Differ. 10, 400–403 (2003).

    CAS  PubMed  Google Scholar 

  98. Terui, T. et al. Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. Cancer Res. 63, 8948–8954 (2003).

    CAS  PubMed  Google Scholar 

  99. Blagosklonny, M. V. et al. Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors. Cancer Res. 65, 7386–7392 (2005). This study describes 'pharmacological rescue of mutant p53' by HDACi, whereby induction of a wild-type p53 transcriptional response occurred in HDACi-treated cells containing mutant p53.

    CAS  PubMed  Google Scholar 

  100. Chen, C., Edelstein, L. C. & Gelinas, C. The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol. Cell Biol. 20, 2687–2695 (2000).

    PubMed  PubMed Central  Google Scholar 

  101. Stehlik, C. et al. Nuclear factor (NF)-κB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor α-induced apoptosis. J. Exp. Med. 188, 211–26 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kramer, O. H. et al. Acetylation of Stat1 modulates NF-κB activity. Genes Dev. 20, 473–485 (2006).

    PubMed  PubMed Central  Google Scholar 

  103. Medina, V. et al. Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway. Cancer Res. 57, 3697–3707 (1997).

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. 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. 277, 2073–2080 (2002).

    CAS  PubMed  Google Scholar 

  106. Glozak, M. A., Sengupta, N., Zhang, X. & Seto, E. Acetylation and deacetylation of non-histone proteins. Gene 363, 15–23 (2005).

    CAS  PubMed  Google Scholar 

  107. Cohen, H. Y. et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol. Cell 13, 627–638 (2004).

    CAS  PubMed  Google Scholar 

  108. Subramanian, C., Opipari, A. W., Jr., Bian, X., Castle, V. P. & Kwok, R. P. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 102, 4842–4847 (2005). Reference 107 identified a link between acetylation of the non-histone protein, Ku70, and induction of apoptosis; reference 108 subsequently demonstrated that Ku70 acetylation is crucial for HDACi-mediated apoptosis.

    CAS  PubMed  Google Scholar 

  109. Canettieri, G. et al. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Nature Struct. Biol. 10, 175–181 (2003).

    CAS  PubMed  Google Scholar 

  110. Brush, M. H., Guardiola, A., Connor, J. H., Yao, T. P. & Shenolikar, S. Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases. J. Biol. Chem. 279, 7685–7691 (2004).

    CAS  PubMed  Google Scholar 

  111. Chen, C. S., Weng, S. C., Tseng, P. H. & Lin, H. P. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J. Biol. Chem. 280, 38879–38887 (2005).

    CAS  PubMed  Google Scholar 

  112. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761–772 (2005).

    CAS  Google Scholar 

  113. Budillon, A., Bruzzese, F., Di Gennaro, E. & Caraglia, M. Multiple-target drugs: inhibitors of heat shock protein 90 and of histone deacetylase. Curr. Drug Targets 6, 337–351 (2005).

    CAS  PubMed  Google Scholar 

  114. Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–67 (2005).

    CAS  PubMed  Google Scholar 

  115. Fuino, L. et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol. Cancer Ther. 2, 971–984 (2003).

    CAS  PubMed  Google Scholar 

  116. Nimmanapalli, R. et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr–Abl and induces apoptosis of imatinib mesylate-sensitive or-refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 63, 5126–5135 (2003).

    CAS  PubMed  Google Scholar 

  117. Bali, P. et al. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin. Cancer Res. 10, 4991–4997 (2004).

    CAS  PubMed  Google Scholar 

  118. Yu, X. et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J. Natl Cancer Inst. 94, 504–513 (2002).

    CAS  PubMed  Google Scholar 

  119. Hideshima, T. et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc. Natl Acad. Sci. USA 102, 8567–8572 (2005).

    CAS  PubMed  Google Scholar 

  120. Bali, P. et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729–26734 (2005).

    CAS  PubMed  Google Scholar 

  121. Bhalla, K. N. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J. Clin. Oncol. 23, 3971–3993 (2005).

    CAS  PubMed  Google Scholar 

  122. Reynolds, C. P. & Lemons, R. S. Retinoid therapy of childhood cancer. Hematol. Oncol. Clin. North Am. 15, 867–910 (2001).

    CAS  PubMed  Google Scholar 

  123. 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 

  124. 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 paper described functional synergy between HDACi and demethylation agents in reactivating epigenetically silenced genes, and demonstrated the hierarchical nature of epigenetic gene silencing in cancer.

    CAS  PubMed  Google Scholar 

  125. Gore, S. D. et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66, 6361–6369 (2006).

    CAS  PubMed  Google Scholar 

  126. Kim, M. S. et al. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res. 63, 7291–7300 (2003).

    CAS  PubMed  Google Scholar 

  127. Catley, L. et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 102, 2615–2622 (2003).

    CAS  PubMed  Google Scholar 

  128. Chauhan, D. et al. Apaf-1/cytochrome c-independent and Smac-dependent induction of apoptosis in multiple myeloma (MM) cells. J. Biol. Chem. 276, 24453–24456 (2001).

    CAS  PubMed  Google Scholar 

  129. Loprevite, M. et al. In vitro study of CI-994, a histone deacetylase inhibitor, in non-small cell lung cancer cell lines. Oncol. Res. 15, 39–48 (2005).

    CAS  PubMed  Google Scholar 

  130. Pauer, L. R. et al. Phase I study of oral CI-994 in combination with carboplatin and paclitaxel in the treatment of patients with advanced solid tumors. Cancer Invest. 22, 886–896 (2004).

    CAS  PubMed  Google Scholar 

  131. Zhang, X. D., Gillespie, S. K., Borrow, J. M. & Hersey, P. The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Mol. Cancer Ther. 3, 425–435 (2004).

    CAS  PubMed  Google Scholar 

  132. Nakata, S. et al. Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene 23, 6261–6271 (2004).

    CAS  PubMed  Google Scholar 

  133. Inoue, S. et al. Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ. 11 (Suppl. 2), S193–S206 (2004).

    CAS  PubMed  Google Scholar 

  134. Rosato, R. R., Almenara, J. A., Dai, Y. & Grant, S. Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol. Cancer Ther. 2, 1273–1284 (2003).

    CAS  PubMed  Google Scholar 

  135. Guo, F. et al. Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res. 64, 2580–2589 (2004).

    CAS  PubMed  Google Scholar 

  136. Singh, T. R., Shankar, S. & Srivastava, R. K. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24, 4609–4623 (2005).

    CAS  PubMed  Google Scholar 

  137. Watanabe, K., Okamoto, K. & Yonehara, S. Sensitization of osteosarcoma cells to death receptor-mediated apoptosis by HDAC inhibitors through downregulation of cellular FLIP. Cell Death Differ. 12, 10–18 (2005).

    CAS  PubMed  Google Scholar 

  138. Kim, E. H. et al. Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene 24, 6877–6889 (2005).

    CAS  PubMed  Google Scholar 

  139. Earel, J. K., Jr., VanOosten, R. L. & Griffith, T. S. Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res. 66, 499–507 (2006).

    CAS  PubMed  Google Scholar 

  140. Rosato, R. R., Almenara, J. A., Yu, C. & Grant, S. Evidence of a functional role for p21WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. Mol. Pharmacol. 65, 571–581 (2004).

    CAS  PubMed  Google Scholar 

  141. Rahmani, M. et al. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Oncogene 22, 6231–6242 (2003).

    CAS  PubMed  Google Scholar 

  142. Yu, C., Dasmahapatra, G., Dent, P. & Grant, S. Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells. Leukemia 19, 1579–1589 (2005).

    CAS  PubMed  Google Scholar 

  143. Deininger, M., Buchdunger, E. & Druker, B. J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105, 2640–2653 (2005).

    CAS  PubMed  Google Scholar 

  144. Yu, C. et al. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and-resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res. 63, 2118–2126 (2003).

    CAS  PubMed  Google Scholar 

  145. Nimmanapalli, R., Fuino, L., Stobaugh, C., Richon, V. & Bhalla, K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101, 3236–3239 (2003).

    CAS  PubMed  Google Scholar 

  146. Kim, J. S. et al. Apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades. Br. J. Haematol. 124, 166–178 (2004).

    CAS  PubMed  Google Scholar 

  147. George, P. et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 105, 1768–1776 (2005).

    CAS  PubMed  Google Scholar 

  148. Kawano, T. et al. Depsipeptide enhances imatinib mesylate-induced apoptosis of Bcr-Abl-positive cells and ectopic expression of cyclin D1, c-Myc or active MEK abrogates this effect. Anticancer Res. 24, 2705–2712 (2004).

    CAS  PubMed  Google Scholar 

  149. Rahmani, M. et al. Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. Cancer Res. 63, 8420–8427 (2003).

    CAS  PubMed  Google Scholar 

  150. Rahmani, M. et al. Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. Mol. Pharmacol. 67, 1166–1176 (2005).

    CAS  PubMed  Google Scholar 

  151. Yu, C. et al. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102, 3765–3774 (2003).

    CAS  PubMed  Google Scholar 

  152. Pei, X. Y., Dai, Y. & Grant, S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin. Cancer Res. 10, 3839–3852 (2004).

    CAS  PubMed  Google Scholar 

  153. Adachi, M. et al. Synergistic effect of histone deacetylase inhibitors FK228 and m-carboxycinnamic acid bis-hydroxamide with proteasome inhibitors PSI and PS-341 against gastrointestinal adenocarcinoma cells. Clin. Cancer Res. 10, 3853–3862 (2004).

    CAS  PubMed  Google Scholar 

  154. Nawrocki, S. T. et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res. 66, 3773–3781 (2006).

    CAS  PubMed  Google Scholar 

  155. Wang, X. et al. 17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-κB pathway. Cancer Res. 66, 1089–1095 (2006).

    CAS  PubMed  Google Scholar 

  156. Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003). This study identified HDAC6 as a key component of the aggresome and describes a functional role for HDAC6 in the clearance of misfolded protein aggregates.

    CAS  PubMed  Google Scholar 

  157. Kopito, R. R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530 (2000).

    CAS  PubMed  Google Scholar 

  158. Zhang, Y., Jung, M. & Dritschilo, A. Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat. Res. 161, 667–674 (2004).

    CAS  PubMed  Google Scholar 

  159. Kim, J. H., Shin, J. H. & Kim, I. H. Susceptibility and radiosensitization of human glioblastoma cells to trichostatin A, a histone deacetylase inhibitor. Int. J. Radiat. Oncol. Biol. Phys. 59, 1174–1180 (2004).

    CAS  PubMed  Google Scholar 

  160. Camphausen, K., Scott, T., Sproull, M. & Tofilon, P. J. Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation. Clin. Cancer Res. 10, 6066–6071 (2004).

    CAS  PubMed  Google Scholar 

  161. Camphausen, K. et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int. J. Cancer 114, 380–36 (2005).

    CAS  PubMed  Google Scholar 

  162. Nome, R. V. et al. Cell cycle checkpoint signaling involved in histone deacetylase inhibition and radiation-induced cell death. Mol. Cancer Ther. 4, 1231–1238 (2005).

    CAS  PubMed  Google Scholar 

  163. Karagiannis, T. C., Kn, H. & El-Osta, A. The Histone Deacetylase Inhibitor, Trichostatin A, Enhances Radiation Sensitivity and Accumulation of γH2A. X. Cancer Biol. Ther. 4, 787–793 (2005).

    CAS  PubMed  Google Scholar 

  164. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    CAS  Google Scholar 

  165. Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    CAS  PubMed  Google Scholar 

  166. 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).

    CAS  PubMed  Google Scholar 

  167. Munshi, A. et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin. Cancer Res. 11, 4912–4922 (2005).

    CAS  PubMed  Google Scholar 

  168. Yaneva, M., Li, H., Marple, T. & Hasty, P. Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor. Nucleic Acids Res. 33, 5320–5330 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Chung, Y. L., Wang, A. J. & Yao, L. F. Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: Implications for increasing therapeutic gain in cancer radiotherapy. Mol. Cancer Ther. 3, 317–325 (2004).

    CAS  PubMed  Google Scholar 

  170. Vannini, A. et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl Acad. Sci. USA 101, 15064–15069 (2004).

    CAS  PubMed  Google Scholar 

  171. Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002).

    CAS  PubMed  Google Scholar 

  172. Gao, L., Cueto, M. A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002).

    CAS  PubMed  Google Scholar 

  173. Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    CAS  PubMed  Google Scholar 

  174. Cory, S. & Adams, J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev. Cancer 2, 647–656 (2002).

    CAS  Google Scholar 

  175. Cory, S., Huang, D. C. & Adams, J. M. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22, 8590–8607 (2003).

    CAS  PubMed  Google Scholar 

  176. Butler, L. M. et al. Inhibition of transformed cell growth and induction of cellular differentiation by pyroxamide, an inhibitor of histone deacetylase. Clin. Cancer Res. 7, 962–970 (2001).

    CAS  PubMed  Google Scholar 

  177. Park, J. H. et al. Class I histone deacetylase-selective novel synthetic inhibitors potently inhibit human tumor proliferation. Clin. Cancer Res. 10, 5271–5281 (2004).

    CAS  PubMed  Google Scholar 

  178. 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).

    CAS  PubMed  Google Scholar 

  179. Kwon, H. J., Owa, T., Hassig, C. A., Shimada, J. & Schreiber, S. L. Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc. Natl Acad. Sci. USA 95, 3356–3361 (1998).

    CAS  PubMed  Google Scholar 

  180. Imai, T. et al. FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells. Oncogene 22, 9231–9242 (2003).

    CAS  PubMed  Google Scholar 

  181. Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med. 11, 77–84 (2005).

    CAS  PubMed  Google Scholar 

  182. Sutheesophon, K. et al. Involvement of the tumor necrosis factor (TNF)/TNF receptor system in leukemic cell apoptosis induced by histone deacetylase inhibitor depsipeptide (FK228). J. Cell Physiol. 203, 387–397 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  184. Rosato, R. R. et al. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol. Pharmacol. 69, 216–225 (2006).

    CAS  PubMed  Google Scholar 

  185. Mitsiades, C. S. et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl Acad. Sci. USA 101, 540–545 (2004).

    CAS  PubMed  Google Scholar 

  186. Peart, M. J. et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc. Natl. Acad. Sci. USA 102, 3697–3702 (2005).

    CAS  PubMed  Google Scholar 

  187. Moore, P. S. et al. Gene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells. Biochim. Biophys. Acta 1693, 167–176 (2004). References 185–187 describe gene-expression profiling analyses of tumour cell lines, undertaken to identify genes that are regulated by structurally diverse HDACi.

    CAS  PubMed  Google Scholar 

  188. Duan, H., Heckman, C. A. & BOX er, L. M. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol. Cell Biol. 25, 1608–1619 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Tan, J. et al. Apoptosis signal-regulating kinase 1 is a direct target of E2F1 and contributes to histone deacetylase inhibitor- induced apoptosis through positive feedback regulation of E2F1 apoptotic activity. J. Biol. Chem. 281, 10508–10515 (2006).

    CAS  PubMed  Google Scholar 

  190. Rahmani, M. et al. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res. 65, 2422–2432 (2005).

    CAS  PubMed  Google Scholar 

  191. Ungerstedt, J. S. et al. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 102, 673–678 (2005).

    CAS  PubMed  Google Scholar 

  192. Butler, L. M. et al. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc. Natl Acad. Sci. USA 99, 11700–11705 (2002).

    CAS  PubMed  Google Scholar 

  193. Zhu, W. G. & Otterson, G. A. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr. Med. Chem. Anti-Canc Agents 3, 187–199 (2003).

    CAS  Google Scholar 

  194. Keen, J. C. et al. A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine. Breast Cancer Res. Treat 81, 177–186 (2003).

    CAS  PubMed  Google Scholar 

  195. Shaker, S., Bernstein, M., Momparler, L. F. & Momparler, R. L. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2′-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk. Res. 27, 437–444 (2003).

    CAS  PubMed  Google Scholar 

  196. Klisovic, M. I. et al. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukemia 17, 350–358 (2003).

    CAS  PubMed  Google Scholar 

  197. Boivin, A. J., Momparler, L. F., Hurtubise, A. & Momparler, R. L. Antineoplastic action of 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells. Anticancer Drugs 13, 869–874 (2002).

    CAS  PubMed  Google Scholar 

  198. Minucci, S. et al. A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells. Proc. Natl Acad. Sci. USA 94, 11295–11300 (1997).

    CAS  PubMed  Google Scholar 

  199. Kitazono, M., Bates, S., Fok, P., Fojo, T. & Blagosklonny, M. V. The histone deacetylase inhibitor FR901228 (desipeptide) restores expression and function of pseudo-null p53. Cancer Biol. Ther. 1, 665–668 (2002).

    CAS  PubMed  Google Scholar 

  200. Zhang, X. D., Gillespie, S. K., Borrow, J. M. & Hersey, P. The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Biochem. Pharmacol. 66, 1537–1545 (2003).

    CAS  PubMed  Google Scholar 

  201. Nguyen, D. M. et al. Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Clin. Cancer Res. 10, 1813–1825 (2004).

    CAS  PubMed  Google Scholar 

  202. 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 

  203. Almenara, J., Rosato, R. & Grant, S. Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 16, 1331–1343 (2002).

    CAS  PubMed  Google Scholar 

  204. Dai, Y., Rahmani, M., Dent, P. & Grant, S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol. Cell Biol. 25, 5429–5444 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Garcia-Manero, G. et al. A Phase I study of the histone deacetylase inhibitor MGCD0103 (MG-0103) given as a three-times weekly oral dose in patients with leukemia or myelodysplastic syndromes (MDS). Blood 106 A4639 (2005).

    Google Scholar 

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Acknowledgements

We apologise to those whose work was not cited or discussed due to space limitations. We thank R. Lindemann and other members of the Johnstone laboratory for helpful discussions. R.W.J. is a Pfizer Australia Research Fellow and is supported by the National Health and Medical Research Council of Australia, the Cancer Council Victoria and the Leukaemia Foundation of Australia. J.E.B. is supported by The Cancer Research Institute Predoctoral Emphasis Pathway in Tumor Immunology.

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Correspondence to Ricky W. Johnstone.

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The Johnstone laboratory receives research funding from Merck and Novartis.

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FURTHER INFORMATION

Clinical Trails Homepage

Glossary

Tumour-suppressor gene

Genes that inhibit cell-cycle progression or induce apoptosis to regulate cell numbers. Often mutated or functionally inactivated in cancer.

Oncogene

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

Epigenetic

Reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA.

Remodelling of chromatin

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.

Apoptosis

Also termed programmed cell death, apoptosis is characterized morphologically by membrane blebbing, chromatin condensation, loss of cell volume and DNA fragmentation, and biochemically by caspase activation.

Chromosomal translocation

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.

RARα

Retinoic acid receptor-α.

PML

Promyelocytic leukaemia.

PLZF

Promyelocytic leukaemia zinc finger.

AML1

Acute myeloid leukaemia 1.

ETO

Eight twenty one protein.

Leukaemia

Chronic or acute haemopoietic cancer 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.

Short interfering RNA

(siRNA). A class of 20–25 nucleotide-long RNA molecules that interfere with the expression of a specific gene.

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.

TRAIL

TNF-related apoptosis-inducing ligand.

APAF1

Apoptotic peptidase activating factor.

HTRA2

High-temperature requirement protein A2.

SMAC

Second mitochondria-derived activator of caspase.

MCL1

Myeloid cell leukaemia sequence 1.

Reactive oxygen species

(ROS). Include oxygen ions, free radicals and peroxides (both inorganic and organic) that are highly reactive because of the presence of unpaired valence shell electrons. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signalling. During times of environmental stress ROS levels can increase dramatically, which can result in significant damage to cell structures.

Checkpoint

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

Heterochromatin

Areas of a chromosome that are genetically silent because they either lack genes or contain genes that are hypoacetylated and transcriptionally repressed.

Angiogenesis

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

TIMP

Tissue inhibitor of MMP.

RECK

Reversion-inducing cysteine-rich protein with kazal motifs.

Metastasis

A secondary cancerous growth formed by transmission of cancer cells from a primary growth located elsewhere in the body usually by way of blood vessels or lymphatics.

Graft-versus-host disease

An immune reaction of transplanted cells against host tissues that possess an antigen not possessed by the donor.

IC50

The half maximal inhibitory concentration. Represents the concentration of an inhibitor that is required for 50% inhibition of a biological or molecular process.

Caspases

A family of cysteine proteases that cleave a variety of cellular substrates leading to the morphological changes associated with apoptosis. Caspases can also activate inflammatory cytokines such as IL-1.

Proteasome

A barrel-shaped multi-protein complex that can specifically digest ubiquitinylated proteins into short polypeptides and amino acids in an ATP-dependent manner.

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Bolden, J., Peart, M. & Johnstone, R. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5, 769–784 (2006). https://doi.org/10.1038/nrd2133

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