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Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Key Points

  • Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes that are responsible for deacetylating and acetylating, respectively, the amino-terminal tails of histones. These chromatin changes regulate transcription and many other nuclear events.

  • Non-histone proteins (such as the oncosuppressor p53) and several cytoplasmic proteins are also regulated by HATs/HDACs.

  • Studies on the molecular pathogenesis of acute myeloid leukaemias have shown that the aberrant recruitment of HDACs has an important role in leukaemogenesis.

  • Leukaemia-associated fusion proteins (such as promyelocytic leukaemia (PML)–retinoic acid receptor (RAR) and acute myeloid leukaemia 1 (AML1)–ETO) recruit HDACs to repress the transcription of genes involved in differentiation (the fusion proteins therefore block differentiation) and impair the function of p53.

  • Alterations in the expression and/or activity of HATs/HDACs have been also observed in solid tumours. Solid tumours show decreased levels of histone acetylation, which correlates with clinical outcome.

  • HDAC inhibitors (HDACi) have been widely studied and belong to several chemical classes.

  • HDACi exert cell-type-specific effects inducing apoptosis, cell-cycle arrest, and differentiation.

  • In leukaemias, HDACi induce the expression of members of the tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL) and FAS death receptor pathways. This induction is responsible for the pro-apoptotic effects of HDACi.

  • Clinical trials for several HDACi have started, and HDACi-responsive tumours have been observed.

Abstract

Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.

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Figure 1: The acetylome.
Figure 2: A model for the deregulated action of HDACs on chromatin in APL and in other cancer cells.
Figure 3: HDAC inhibitors.
Figure 4: Tumour-selective action of HDACi in acute promyelocytic leukaemia.

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References

  1. Blander, G. & Guarente, L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 73, 417–435 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Leipe, D. D. & Landsman, D. Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are members of an ancient protein superfamily. Nucleic Acids Res. 25, 3693–3997 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kouzarides, T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 19, 1176–1179 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Richmond, T. J. & Davey, C. A. The structure of DNA in the nucleosome core. Nature 423, 145–150 (2003).

    CAS  PubMed  Google Scholar 

  6. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    CAS  Google Scholar 

  7. Turner, B. M. Cellular memory and the histone code. Cell 111, 285–291 (2002). References 6 and 7 contain the proposal and one of the counter-proposals of the histone code.

    CAS  PubMed  Google Scholar 

  8. Turner, B. M. Reading signals on the nucleosome with a new nomenclature for modified histones. Nature Struct. Mol. Biol. 12, 110–112 (2005).

    CAS  Google Scholar 

  9. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    CAS  PubMed  Google Scholar 

  10. Polo, S. E. & Almouzni, G. Histone metabolic pathways and chromatin assembly factors as proliferation markers. Cancer Lett. 220, 1–9 (2005).

    CAS  PubMed  Google Scholar 

  11. Vidanes, G. M., Bonilla, C. Y. & Toczyski, D. P. Complicated tails: histone modifications and the DNA damage response. Cell 121, 973–976 (2005).

    CAS  PubMed  Google Scholar 

  12. Weinreich, M., Palacios DeBeer, M. A. & Fox, C. A. The activities of eukaryotic replication origins in chromatin. Biochim. Biophys. Acta 1677, 142–157 (2004).

    CAS  PubMed  Google Scholar 

  13. Zhang, J., Xu, F., Hashimshony, T., Keshet, I. & Cedar, H. Establishment of transcriptional competence in early and late S phase. Nature 420, 198–202 (2002).

    CAS  PubMed  Google Scholar 

  14. Mann, M. & Jensen, O. N. Proteomic analysis of post-translational modifications. Nature Biotechnol. 21, 255–261 (2003).

    CAS  Google Scholar 

  15. Qiang, L., Xiao, H., Campos, E. I., Ho, V. C. & Li, G. Development of a PAN-specific, affinity-purified anti-acetylated lysine antibody for detection, identification, isolation, and intracellular localization of acetylated protein. J. Immunoassay Immunochem. 26, 13–23 (2005).

    CAS  PubMed  Google Scholar 

  16. Ronzoni, S., Faretta, M., Ballarini, M., Pelicci, P. & Minucci, S. New method to detect histone acetylation levels by flow cytometry. Cytometry A 66, 52–61 (2005).

    PubMed  Google Scholar 

  17. Caron, C., Boyault, C. & Khochbin, S. Regulatory cross-talk between lysine acetylation and ubiquitination: role in the control of protein stability. Bioessays 27, 408–415 (2005).

    CAS  PubMed  Google Scholar 

  18. Giandomenico, V., Simonsson, M., Grönroos, E. & Ericsson, J. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol. Cell. Biol. 23, 2587–2599 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Grönroos, E., Hellman, U., Heldin, C. H. & Ericsson, J. Control of Smad7 stability by competition between acetylation and ubiquitination. Mol. Cell 10, 483–493 (2002).

    PubMed  Google Scholar 

  20. Jin, Y. H. et al. Transforming growth factor-β stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J. Biol. Chem. 279, 29409–29417 (2004).

    CAS  PubMed  Google Scholar 

  21. Rausa, F. M., Hughes, D. E. & Costa, R. H. Stability of the hepatocyte nuclear factor 6 transcription factor requires acetylation by the CREB-binding protein coactivator. J. Biol. Chem. 279, 43070–43076 (2004).

    CAS  PubMed  Google Scholar 

  22. Munshi, N et al. Coordination of a transcriptional switch by HMGI(Y) acetylation. Science 293, 1133–1136 (2001).

    CAS  PubMed  Google Scholar 

  23. 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 

  24. Wang, R., Cherukuri, P. & Luo, J. Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation. J. Biol. Chem. 280, 11528–11534 (2005).

    CAS  PubMed  Google Scholar 

  25. Jeong, J. W. et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111, 709–7020 (2002).

    CAS  PubMed  Google Scholar 

  26. Bilton, R. et al. Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1α and is not induced by hypoxia or HIF. J. Biol. Chem. 280, 31132–31140 (2005).

    CAS  PubMed  Google Scholar 

  27. Cohen HY, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol. Cell 13, 627–638 (2004). Cytoplasmic role for acetylation of Ku70 in apoptosis.

    CAS  PubMed  Google Scholar 

  28. Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).

    CAS  PubMed  Google Scholar 

  29. Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bannister, A. J., Miska, E. A., Görlich, D. & Kouzarides, T. Acetylation of importin-α nuclear import factors by CBP/p300. Curr. Biol. 10, 467–470 (2000).

    CAS  PubMed  Google Scholar 

  31. Caillaud, A. et al. Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding. J. Biol. Chem. 277, 49417–49421 (2002).

    CAS  PubMed  Google Scholar 

  32. Choi, C. H., Hiromura, M. & Usheva, A. Transcription factor IIB acetylates itself to regulate transcription. Nature 424, 965–969 (2003).

    CAS  PubMed  Google Scholar 

  33. Hasan, S. et al. Acetylation regulates the DNA end-trimming activity of DNA polymerase β. Mol. Cell 10, 1213–1222 (2002).

    CAS  PubMed  Google Scholar 

  34. Hasan, S. et al. Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol. Cell 7, 1221–1231 (2001).

    CAS  PubMed  Google Scholar 

  35. Bode, A. M. & Dong, Z. Post-translational modification of p53 in tumorigenesis. Nature Rev. Cancer 4, 793–805 (2004).

    CAS  Google Scholar 

  36. Chen, L. F. & Greene, W. C. Shaping the nuclear action of NF-κB. Nature Rev. Mol. Cell Biol. 5, 392–401 (2004).

    CAS  Google Scholar 

  37. Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003).

    CAS  PubMed  Google Scholar 

  38. Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601–607 (2005). Role of acetylation in the control of the chaperone function of HSP90.

    CAS  PubMed  Google Scholar 

  39. Lagger, G. et al. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21, 2672–2681 (2002). Genetic demonstration that HDAC1 is essential for proliferation in mammals.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Vega, R. B. et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119, 555–566 (2004).

    CAS  PubMed  Google Scholar 

  42. Minucci, S., Nervi, C., Lo Coco, F. & Pelicci, P. G. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene 20, 3110–3115 (2001).

    CAS  PubMed  Google Scholar 

  43. Warrell, R. P. et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324, 1385–1393 (1991).

    PubMed  Google Scholar 

  44. Minucci, S. & Pelicci, P. G. Retinoid receptors in health and disease: co-regulators and the chromatin connection. Semin. Cell Dev. Biol. 10, 215–225 (1999).

    CAS  PubMed  Google Scholar 

  45. Lin, R. J., Egan, D. A. & Evans, R. M. Molecular genetics of acute promyelocytic leukemia. Trends Genet. 15, 179–184 (1999).

    CAS  PubMed  Google Scholar 

  46. Lin, R. J. & Evans, R. M. Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol. Cell 5, 821–830 (2000).

    CAS  PubMed  Google Scholar 

  47. Minucci, S. et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol. Cell 5, 811–820 (2000).

    CAS  PubMed  Google Scholar 

  48. Di Croce, L. et al. Altered epigenetic signals in human disease. Cancer Biol. Ther. 3, 831–837 (2004).

    CAS  PubMed  Google Scholar 

  49. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    CAS  PubMed  Google Scholar 

  50. 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 

  51. Brown, D. et al. A PMLRARα transgene initiates murine acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 2551–2556 (1997).

    CAS  PubMed  Google Scholar 

  52. Grisolano, J. L., Wesselschmidt, R. L., Pelicci, P. G. & Ley, T. J. Altered myeloid development and acute leukemia in transgenic mice expressing PML–RAR α under control of cathepsin G regulatory sequences. Blood 89, 376–387 (1997).

    CAS  PubMed  Google Scholar 

  53. Trecca, D. et al. Analysis of p53 gene mutations in acute myeloid leukemia. Am. J. Hematol. 46, 304–309 (1994).

    CAS  PubMed  Google Scholar 

  54. Insinga, A., Pelicci, P. G. & Minucci, S. Leukemia-associated fusion proteins. Multiple mechanisms of action to drive cell transformation. Cell Cycle 4, 67–69 (2005).

    CAS  PubMed  Google Scholar 

  55. Insinga, A. et al. Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J. 23, 1144–1154 (2004). Demonstrates that deacetylation of non-histone substrates (p53) by HDACs has a role in tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).

    CAS  PubMed  Google Scholar 

  57. Eckner, R., Arany, Z., Ewen, M., Sellers, W. & Livingston, D. M. The adenovirus E1A-associated 300-kD protein exhibits properties of a transcriptional coactivator and belongs to an evolutionarily conserved family. Cold Spring Harb. Symp. Quant. Biol. 59, 85–95 (1994).

    CAS  PubMed  Google Scholar 

  58. Iyer, N. G., Ozdag, H. & Caldas, C. p300/CBP and cancer. Oncogene 23, 4225–4231 (2004).

    CAS  PubMed  Google Scholar 

  59. Kumar, R., Wang, R. A. & Bagheri-Yarmand, R. Emerging roles of MTA family members in human cancers. Semin. Oncol. 30, 30–37 (2003).

    CAS  PubMed  Google Scholar 

  60. Bagheri-Yarmand, R., Talukder, A. H., Wang, R. A., Vadlamudi, R. K. & Kumar, R. Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis. Development 131, 3469–3479 (2004).

    CAS  PubMed  Google Scholar 

  61. 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 

  62. Toh, Y. et al. Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. Int. J. Cancer 110, 362–367 (2004).

    CAS  PubMed  Google Scholar 

  63. 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). References 62 and 63 demonstrate that global histone modifications occur in cancer.

    CAS  PubMed  Google Scholar 

  64. Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005). A coordinated pattern of histone modifications predicts clinical outcome in prostate cancer.

    CAS  PubMed  Google Scholar 

  65. Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

    CAS  PubMed  Google Scholar 

  66. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

    CAS  Google Scholar 

  67. Lund, A. H. & van Lohuizen, M. Epigenetics and cancer. Genes Dev. 18, 2315–2335 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  70. Mai, A. et al. Histone deacetylation in epigenetics: an attractive target for anticancer therapy. Med. Res. Rev. 25, 261–309 (2005).

    CAS  PubMed  Google Scholar 

  71. Miller, T. A., Witter, D. J. & Belvedere, S. Histone deacetylase inhibitors. J. Med. Chem. 46, 5097–5116 (2003).

    CAS  PubMed  Google Scholar 

  72. 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 

  73. Mai, A. et al. Discovery of (aryloxopropenyl)pyrrolyl hydroxyamides as selective inhibitors of class IIa histone deacetylase homologue HD1-A. J. Med. Chem. 46, 4826–4829 (2003).

    CAS  PubMed  Google Scholar 

  74. Heltweg, B. et al. Subtype selective substrates for histone deacetylases. J. Med. Chem. 47, 5235–5243 (2004).

    CAS  PubMed  Google Scholar 

  75. 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 

  76. Finnin, M. S. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).

    CAS  PubMed  Google Scholar 

  77. Richon, V. M. et al. Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo. Methods Enzymol. 376, 199–205 (2004).

    CAS  PubMed  Google Scholar 

  78. Somoza, J. R. et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure (Camb) 12, 1325–1334 (2004).

    CAS  Google Scholar 

  79. 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). References 78 and 79 show the structural analysis of mammalian HDAC8 in complex with HDACi.

    CAS  PubMed  Google Scholar 

  80. Siddiqui, H., Solomon, D. A., Gunawardena, R. W., Wang, Y. & Knudsen, E. S. Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition. Mol. Cell. Biol. 23, 7719–7731 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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 

  82. 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 

  83. 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 

  84. Van Lint, C., Emiliani, S. & Verdin, E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr. 5, 245–253 (1996). References 81–84 detail gene-profiling studies of the cell transcriptional response to HDACi in different model systems. The results are not always fully consistent among the different systems (the number of modulated genes varies from <5% to 20%).

    CAS  PubMed  Google Scholar 

  85. Camphausen, K. et al. Enhanced radiation-induced cell killing and prolongation of gH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res. 64, 316–321 (2004).

    CAS  PubMed  Google Scholar 

  86. 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 

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

    CAS  PubMed  Google Scholar 

  88. Beamish, H., Warrener, R. & Gabrielli, B. G. Analysis of checkpoint responses to histone deacetylase inhibitors. Methods Mol. Biol. 281, 245–259 (2004).

    CAS  PubMed  Google Scholar 

  89. 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 

  90. 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 

  91. Gui, C. Y., Ngo, L., Xu, W. S, Richon, V. M. & Marks, P. A. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc. Natl Acad. Sci. USA 101, 1241–1246 (2004).

    CAS  PubMed  Google Scholar 

  92. Varshochi, R. et al. ICI182,780 induces p21Waf1 gene transcription through releasing histone deacetylase 1 and estrogen receptor α from Sp1 sites to induce cell cycle arrest in MCF-7 breast cancer cell line. J. Biol. Chem. 280, 3185–3196 (2005).

    CAS  PubMed  Google Scholar 

  93. Archer, S. Y., Meng, S., Shei, A. & Hodin, R. A. p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc. Natl Acad. Sci. USA 95, 6791–6796 (1998).

    CAS  PubMed  Google Scholar 

  94. Shao, Y., Gao, Z., Marks, P. A. & Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 101, 18030–18035 (2004).

    CAS  PubMed  Google Scholar 

  95. 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 (2005).

    Google Scholar 

  96. 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 

  97. Subramanian, C., Opipari, A. W., 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).

    CAS  PubMed  Google Scholar 

  98. Atadja, P. et al. Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Novartis Found. Symp. 259, 249–266 (2004).

    CAS  PubMed  Google Scholar 

  99. 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 

  100. 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 

  101. 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).

    CAS  PubMed  Google Scholar 

  102. Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med. 11, 77–84 (2005). References 101 and 102 demonstrate the essential role of induction of the TRAIL pathway for the pro-apoptotic response following HDACi treatment in leukaemias.

    CAS  PubMed  Google Scholar 

  103. Inoue, H. et al. Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. Int. J. Mol. Med. 9, 521–525 (2002).

    CAS  PubMed  Google Scholar 

  104. 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 

  105. 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 

  106. 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 

  107. Rosato, R. R. & Grant, S. Histone deacetylase inhibitors in clinical development. Expert Opin. Investig. Drugs 13, 21–38 (2004).

    CAS  PubMed  Google Scholar 

  108. 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 

  109. Drummond, D. C. et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 45, 495–528 (2004).

    Google Scholar 

  110. Chavez-Blanco, A. et al. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Mol. Cancer 4, 22 (2005).

    PubMed  PubMed Central  Google Scholar 

  111. Kelly, W. K. et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 23, 3923–3931 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kelly, W. K. et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 9, 3578–3588 (2003).

    CAS  PubMed  Google Scholar 

  113. Ryan, Q. C. et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J. Clin. Oncol. 23, 3912–3922 (2005).

    CAS  PubMed  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. Sandor, V. et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin. Cancer Res. 8, 718–728 (2002).

    CAS  PubMed  Google Scholar 

  116. Piekarz, R. L. et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood 103, 4636–4643 (2004).

    CAS  PubMed  Google Scholar 

  117. Bandyopadhyay, D., Mishra, A. & Medrano, E. E. Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway. Cancer Res. 64, 7706–7710 (2004).

    CAS  PubMed  Google Scholar 

  118. Xiao, J. J. et al. Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J. Pharmacol. Exp. Ther. 314, 467–475 (2005).

    CAS  PubMed  Google Scholar 

  119. Pilatrino, C. et al. Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer 104, 101–109 (2005).

    CAS  PubMed  Google Scholar 

  120. Cameron, E. E., Bachman, K. E., Myöhänen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21, 103–107 (1999).

    CAS  PubMed  Google Scholar 

  121. 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 

  122. Girdwood, D. W., Tatham, M. H. & Hay, R. T. SUMO and transcriptional regulation. Semin. Cell Dev. Biol. 15, 201–210 (2004).

    CAS  PubMed  Google Scholar 

  123. Al-Hajj, M., Becker, M. W., Wicha, M., Weissman, I. & Clarke, M. F. Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47 (2004).

    CAS  PubMed  Google Scholar 

  124. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    CAS  PubMed  Google Scholar 

  125. Milhem, M. et al. Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A. Blood 103, 4102–4110 (2004). An initial study on the effects of HDACi on stem cells.

    CAS  PubMed  Google Scholar 

  126. Guenther, M. G. et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Huang, E. Y. et al. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev. 14, 45–54 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).

    CAS  PubMed  Google Scholar 

  129. Jones, P. L., Sachs, L. M., Rouse, N., Wade, P. A. & Shi, Y. B. Multiple N-CoR complexes contain distinct histone deacetylases. J. Biol. Chem. 276, 8807–8811 (2001).

    CAS  PubMed  Google Scholar 

  130. Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861 (1998).

    CAS  PubMed  Google Scholar 

  132. Yao, Y. L. & Yang, W. M. The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity. J. Biol. Chem. 278, 42560–42568 (2003).

    CAS  PubMed  Google Scholar 

  133. Zhang, Y. et al. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Seigneurin-Berny, D. et al. Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol. Cell. Biol. 21, 8035–8044 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Yamagoe, S. et al. Interaction of histone acetylases and deacetylases in vivo. Mol. Cell. Biol. 23, 1025–1033 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 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 

  137. Verdin, E., Dequiedt, F. & Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 19, 286–293 (2003).

    CAS  PubMed  Google Scholar 

  138. Gore, S. D. et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin. Cancer Res. 8, 963–970 (2002).

    CAS  PubMed  Google Scholar 

  139. Patnaik, A. et al. A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. Clin. Cancer Res. 8, 2142–2148 (2002).

    CAS  PubMed  Google Scholar 

  140. Raffoux, E., Chaibi, P., Dombret, H. & Degos, L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 90, 986–988 (2005).

    CAS  PubMed  Google Scholar 

  141. Byrd, J. C. et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105, 959–967 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge Bruno Amati, Gordon McVie, Antonello Mai, Michela Prudenziati, Roberta Carbone Jr, Gabriele Bucci, Oronzina Botrugno, Maurizio Moroni, members of our laboratories for discussions and critical reading of the manuscript, and the reviewers of this manuscript for their insightful comments.

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Correspondence to Saverio Minucci.

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Competing interests

The authors are shareholders of Genextra, a holding company in the field of biotechnology. One of the scientific programmes of Genextra is the development of novel HDAC inhibitors. None of the molecules studied by Genextra are discussed in this work.

The authors are co-inventors of patents on the use of valproic acid.

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DATABASES

National Cancer Institute

Acute promyelocytic leukaemia

Glossary

Enhanceosome

The assembly of higher-order three-dimensional transcription factor–enhancer DNA complexes that are required to activate a gene.

14-3-3 proteins

These proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signalling proteins, including kinases, phosphatases and transmembrane receptors. Recently, class 2 histone deacetylases have also been shown to interact with members of the 14-3-3 family.

Pharmacophore

The minimum amount of chemical groups or functionality in a drug required to elicit its action.

Maximal tolerated dose

The maximal dosage of a particular drug that can be used before patients show undesired side effects.

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Minucci, S., Pelicci, P. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6, 38–51 (2006). https://doi.org/10.1038/nrc1779

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