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Histone deacetylases: target enzymes for cancer therapy

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Abstract

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups of lysine residues from nucleosomal histones, represents major molecular epigenic mechanisms controlling gene expression. Histone deacetylases (HDACs) and histone acetyl transferases (HAT) represent the two families of enzymes in charge of the control of the level of acetylation of the histone tails. By removing the acetyl groups that abrogate the positive charge of the lysine residues that maintain the histone tails attached to DNA, HDACs repress transcription. In mammals, these latter enzymes form three groups of related enzymes based on their sequence homology and are classified as HDACs I, II and III. Global inhibition of the HDACs I and II groups results in cell growth arrest and apoptosis of cancer cells and alters tumor growth in in vivo experimental models. Their surprisingly low general toxicity and their impressive efficiency in preclinical cancer models has led to consider HDAC inhibitors as very promising new anticancer pharmacological agents. In this review, we attempt to give a comprehensive overview of the role and the involvement of HDAC in carcinogenesis as well as the current progress on the development of HDAC general and specific inhibitors as new cancer therapies.

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References

  1. Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis. Proc Natl Acad Sci USA 51:786–794

    Article  PubMed  CAS  Google Scholar 

  2. Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23

    Article  PubMed  CAS  Google Scholar 

  3. Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411

    Article  PubMed  CAS  Google Scholar 

  4. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749

    Article  PubMed  Google Scholar 

  5. Marks PA, Miller T, Richon VM (2003) Histone deacetylases. Curr Opin Pharmacol 3:344–351

    Article  PubMed  CAS  Google Scholar 

  6. Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262:75–83

    Article  PubMed  CAS  Google Scholar 

  7. Cress WD, Seto E (2000) Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 184:1–16

    Article  PubMed  CAS  Google Scholar 

  8. Timmermann S, Lehrmann H, Polesskaya A, Harel-Bellan A (2001) Histone acetylation and disease. Cell Mol Life Sci 58:728–736

    Article  PubMed  CAS  Google Scholar 

  9. Mahlknecht U, Hoelzer D (2000) Histone acetylation modifiers in the pathogenesis of malignant disease. Mol Med 6:623–644

    PubMed  CAS  Google Scholar 

  10. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM (1998) Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811–814

    Article  PubMed  CAS  Google Scholar 

  11. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG (1998) Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818

    Article  PubMed  CAS  Google Scholar 

  12. Della Ragione F, Criniti V, Della Pietra V, Borriello A, Oliva A, Indaco S, Yamamoto T, Zappia V (2001) Genes modulated by histone acetylation as new effectors of butyrate activity. FEBS Lett 499:199–204

    Article  PubMed  CAS  Google Scholar 

  13. Van Lint C, Emiliani S, Verdin E (1996) The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 5:245–253

    PubMed  Google Scholar 

  14. Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM (2001) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res 61:8492–8497

    PubMed  CAS  Google Scholar 

  15. Mariadason JM, Corner GA, Augenlicht LH (2000) Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res 60:4561–4572

    PubMed  CAS  Google Scholar 

  16. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK (2003) 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

    PubMed  CAS  Google Scholar 

  17. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, Richon VM, Marks PA, Anderson KC (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 101:540–545

    Article  PubMed  CAS  Google Scholar 

  18. Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299

    Article  PubMed  CAS  Google Scholar 

  19. Han JW, Ahn SH, Park SH, Wang SY, Bae GU, Seo DW, Kwon HK, Hong S, Lee HY, Lee YW, Lee HW (2000) Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. Cancer Res 60:6068–6074

    PubMed  CAS  Google Scholar 

  20. Hoshikawa Y, Kwon HJ, Yoshida M, Horinouchi S, Beppu T, Trichostatin A (1994) induces morphological changes and gelsolin expression by inhibiting histone deacetylase in human carcinoma cell lines. Exp Cell Res 214:189–197

    Article  PubMed  CAS  Google Scholar 

  21. Nishida K, Komiyama T, Miyazawa S, Shen ZN, Furumatsu T, Doi H, Yoshida A, Yamana J, Yamamura M, Ninomiya Y, Inoue H, Asahara H (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376

    Article  PubMed  CAS  Google Scholar 

  22. Kosugi H, Towatari M, Hatano S, Kitamura K, Kiyoi H, Kinoshita T, Tanimoto M, Murate T, Kawashima K, Saito H, Naoe T (1999) Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia 13:1316–1324

    Article  PubMed  CAS  Google Scholar 

  23. Huang L, Pardee AB (2000) Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol Med 6:849–866

    PubMed  CAS  Google Scholar 

  24. Yin D, Ong JM, Hu J, Desmond JC, Kawamata N, Konda BM, Black KL, Koeffler HP (2007) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo. Clin Cancer Res 13:1045–1052

    Article  PubMed  CAS  Google Scholar 

  25. Rocchi P, Tonelli R, Camerin C, Purgato S, Fronza R, Bianucci F, Guerra F, Pession A, Ferreri AM (2005) p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol Rep 13:1139–1144

    PubMed  CAS  Google Scholar 

  26. Kim S, Kang JK, Kim YK, Seo DW, Ahn SH, Lee JC, Lee CH, You JS, Cho EJ, Lee HW, Han JW (2006) Histone deacetylase inhibitor apicidin induces cyclin E expression through Sp1 sites. Biochem Biophys Res Commun 342:1168–1173

    Article  PubMed  CAS  Google Scholar 

  27. Chen Z, Clark S, Birkeland M, Sung CM, Lago A, Liu R, Kirkpatrick R, Johanson K, Winkler JD, Hu E (2002) Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells. Cancer Lett 188:127–140

    Article  PubMed  CAS  Google Scholar 

  28. Hirose T, Sowa Y, Takahashi S, Saito S, Yasuda C, Shindo N, Furuichi K, Sakai T (2003) p53–independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene 22:7762–7773

    Article  PubMed  CAS  Google Scholar 

  29. Nair AR, Boersma LJ, Schiltz L, Chaudhry MA, Muschel RJ (2001) Paradoxical effects of trichostatin A: inhibition of NF-Y-associated histone acetyltransferase activity, phosphorylation of hGCN5 and downregulation of cyclin A and B1 mRNA. Cancer Lett 166:55–64

    Article  PubMed  CAS  Google Scholar 

  30. Greenberg VL, Williams JM, Cogswell JP, Mendenhall M, Zimmer SG (2001) Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. Thyroid 11:315–325

    Article  PubMed  CAS  Google Scholar 

  31. Noh EJ, Lee JS (2003) Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2–M transition. Biochem Biophys Res Commun 310:267–273

    Article  PubMed  CAS  Google Scholar 

  32. Kim YB, Lee KH, Sugita K, Yoshida M, Horinouchi S (1999) Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 18:2461–2470

    Article  PubMed  CAS  Google Scholar 

  33. Takai N, Desmond JC, Kumagai T, Gui D, Said JW, Whittaker S, Miyakawa I, Koeffler HP (2004) Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res 10:1141–1149

    Article  PubMed  CAS  Google Scholar 

  34. Choi YH (2005) Induction of apoptosis by trichostatin A, a histone deacetylase inhibitor, is associated with inhibition of cyclooxygenase-2 activity in human non-small cell lung cancer cells. Int J Oncol 27:473–479

    PubMed  CAS  Google Scholar 

  35. Gillespie S, Borrow J, Zhang XD, Hersey P (2006) Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis 11:2251–2265

    Article  PubMed  CAS  Google Scholar 

  36. Zhang XD, Gillespie SK, Borrow JM, Hersey P (2004) 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

    PubMed  CAS  Google Scholar 

  37. Sawa H, Murakami H, Kumagai M, Nakasato M, Yamauchi S, Matsuyama N, Tamura Y, Satone A, Ide W, Hashimoto I, Kamada H (2004) Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo. Acta Neuropathol (Berl) 107:523–531

    Article  CAS  Google Scholar 

  38. Maiso P, Carvajal-Vergara X, Ocio EM, Lopez-Perez R, Mateo G, Gutierrez N, Atadja P, Pandiella A, San Miguel JF (2006) The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res 66:5781–5789

    Article  PubMed  CAS  Google Scholar 

  39. Rosato RR, Maggio SC, Almenara JA, Payne SG, Atadja P, Spiegel S, Dent P, Grant S (2006) 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

    PubMed  CAS  Google Scholar 

  40. Cao XX, Mohuiddin I, Ece F, McConkey DJ, Smythe WR (2001) Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma. Am J Respir Cell Mol Biol 25:562–568

    PubMed  CAS  Google Scholar 

  41. Facchetti F, Previdi S, Ballarini M, Minucci S, Perego P, La Porta CA (2004) Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors. Apoptosis 9:573–582

    Article  PubMed  CAS  Google Scholar 

  42. Liu LT, Chang HC, Chiang LC, Hung WC (2003) Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res 63:3069–3072

    PubMed  CAS  Google Scholar 

  43. Vinodhkumar R, Song YS, Ravikumar V, Ramakrishnan G, Devaki T (2007) Depsipeptide a histone deacetlyase inhibitor down regulates levels of matrix metalloproteinases 2 and 9 mRNA and protein expressions in lung cancer cells (A549). Chem Biol Interact 165:220–229

    Article  PubMed  CAS  Google Scholar 

  44. Klisovic DD, Klisovic MI, Effron D, Liu S, Marcucci G, Katz SE (2005) Depsipeptide inhibits migration of primary and metastatic uveal melanoma cell lines in vitro: a potential strategy for uveal melanoma. Melanoma Res 15:147–153

    Article  PubMed  CAS  Google Scholar 

  45. Joseph J, Mudduluru G, Antony S, Vashistha S, Ajitkumar P, Somasundaram K (2004) Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB. Oncogene 23:6304–6315

    Article  PubMed  CAS  Google Scholar 

  46. Chang HC, Liu LT, Hung WC (2004) Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK. Cell Signal 16:675–679

    Article  PubMed  CAS  Google Scholar 

  47. Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV, Castronovo V (2002) Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21:427–436

    Article  PubMed  CAS  Google Scholar 

  48. Kim SH, Ahn S, Han JW, Lee HW, Lee HY, Lee YW, Kim MR, Kim KW, Kim WB, Hong S (2004) Apicidin is a histone deacetylase inhibitor with anti-invasive and anti-angiogenic potentials. Biochem Biophys Res Commun 315:964–970

    Article  PubMed  CAS  Google Scholar 

  49. Kwon HJ, Kim MS, Kim MJ, Nakajima H, Kim KW (2002) Histone deacetylase inhibitor FK228 inhibits tumor angiogenesis. Int J Cancer 97:290–296

    Article  PubMed  CAS  Google Scholar 

  50. Michaelis M, Michaelis UR, Fleming I, Suhan T, Cinatl J, Blaheta RA, Hoffmann K, Kotchetkov R, Busse R, Nau H, Cinatl J Jr (2004) Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol 65:520–527

    Article  PubMed  CAS  Google Scholar 

  51. Mie Lee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, Jeong Kwon H, Kim KW (2003) Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 300:241–246

    Article  PubMed  Google Scholar 

  52. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R (2006) Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 12:634–642

    Article  PubMed  CAS  Google Scholar 

  53. Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R (2004) The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64:6626–6634

    Article  PubMed  CAS  Google Scholar 

  54. Sasakawa Y, Naoe Y, Noto T, Inoue T, Sasakawa T, Matsuo M, Manda T, Mutoh S (2003) Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. Biochem Pharmacol 66:897–906

    Article  PubMed  CAS  Google Scholar 

  55. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443

    Article  PubMed  Google Scholar 

  56. Fish JE, Matouk CC, Rachlis A, Lin S, Tai SC, D’Abreo C, Marsden PA (2005) The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code. J Biol Chem 280:24824–24838

    Article  PubMed  CAS  Google Scholar 

  57. Robb GB, Carson AR, Tai SC, Fish JE, Singh S, Yamada T, Scherer SW, Nakabayashi K, Marsden PA (2004) Post-transcriptional regulation of endothelial nitric-oxide synthase by an overlapping antisense mRNA transcript. J Biol Chem 279:37982–37996

    Article  PubMed  CAS  Google Scholar 

  58. Rossig L, Li H, Fisslthaler B, Urbich C, Fleming I, Forstermann U, Zeiher AM, Dimmeler S (2002) 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

    Article  PubMed  Google Scholar 

  59. Marks PA, Richon VM, Kelly WK, Chiao JH, Miller T (2004) Histone deacetylase inhibitors: development as cancer therapy. Novartis Found Symp 259:269–281 discussion 281–268

    Article  PubMed  CAS  Google Scholar 

  60. Kelly WK, Marks PA (2005) Drug insight: Histone deacetylase inhibitors–development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2:150–157

    Article  PubMed  CAS  Google Scholar 

  61. Kelly WK, O’Connor OA, Marks PA (2002) Histone deacetylase inhibitors: from target to clinical trials. Expert Opin Investig Drugs 11:1695–1713

    Article  PubMed  CAS  Google Scholar 

  62. Park JH, Jong HS, Kim SG, Jung Y, Lee KW, Lee JH, Kim DK, Bang YJ, Kim TY (2007) Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase. J Mol Med

  63. Chen L, Meng S, Wang H, Bali P, Bai W, Li B, Atadja P, Bhalla KN, Wu J (2005) Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther 4:1311–1319

    Article  PubMed  CAS  Google Scholar 

  64. Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res 13:4882–4890

    Article  PubMed  CAS  Google Scholar 

  65. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) 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

    Article  PubMed  CAS  Google Scholar 

  66. Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E (2001) Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo. J Biol Chem 276:35826–35835

    Article  PubMed  CAS  Google Scholar 

  67. Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9:45–57

    Article  PubMed  CAS  Google Scholar 

  68. Mottet D, Bellahcene A, Pirotte S, Waltregny D, Deroanne C, Lamour V, Lidereau R, Castronovo V (2007) HDAC7 Silencing Alters Endothelial Cell Migration, a Key Step in Angiogenesis. Circ Res

  69. Chang S, Young BD, Li S, Qi X, Richardson JA, Olson EN (2006) Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10. Cell 126:321–334

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Grant sponsors include European FP6 (STROMA and METABRE), the National Fund for Scientific Research (Belgium), the Centre Anti-Cancéreux près de l’Université de Liège, the Fonds Léon Frédéricq, TELEVIE. D. Mottet is a Researcher at the F.R.S.-FNRS (Belgium).

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  1. Metastasis Research Laboratory, Centre for Experimental Cancer Research, University of Liège, Pathology Building, B23, -1, 4000, Liege, Belgium

    Denis Mottet & Vincent Castronovo

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Correspondence to Vincent Castronovo.

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Mottet, D., Castronovo, V. Histone deacetylases: target enzymes for cancer therapy. Clin Exp Metastasis 25, 183–189 (2008). https://doi.org/10.1007/s10585-007-9131-5

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