J. Pharm. Technol. Res. Manag.

Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

Kajal Thapa, Savir Kumar, Anurag Sharma, Sandeep Arora Amarjot Kaur Grewal and Thakur Gurjeet Singh*


Epigenetic; Histone; Acetylation; Deacetylation; Lysine; Histone deacetylases inhibitors

PUBLISHED DATE November 2017
PUBLISHER The Author(s) 2017. This article is published with open access at www.chitkara.edu.in/publications

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.

Page(s) 235–253
URL http://dspace.chitkara.edu.in/jspui/bitstream/123456789/671/1/JPTRM%205-2-7.pdf
ISSN Print : 2321-2217, Online : 2321-2225
DOI 10.15415/jptrm.2017.52014
  • Belvedere, S., Witter, D.J., Yan, J., Secrist, J.P., Richon, V. and Miller, T.A., (2007). Aminosuberoyl hydroxamic acids (ASHAs): a potent new class of HDAC inhibitors. Bioorganic & medicinal chemistry letters, 17(14), 3969–3971. https://doi.org/10.1016/j.bmcl.2007.04.
  • Bjerling, P., Silverstein, R.A., Thon, G., Caudy, A., Grewal, S. and Ekwall, K., (2002). Functional divergence between histone deacetylases in fission yeast by distinct cellular localization and in vivo specificity. Molecular and cellular biology, 22(7), 2170–2181. https://doi.org/10.1128/MCB.22.7.2170-2181.2002
  • Bradbury, C.A., Khanim, F.L., Hayden, R., Bunce, C.M., White, D.A., Drayson, M.T., Craddock, C. and Turner, B.M., (2005). Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia, 19(10), 1751. https://doi.org/10.1038/sj.leu.2403910
  • Cha, M.K., Suh, K.H. and Kim, I.H., (2009). Overexpression of peroxiredoxin I and thioredoxin1 in human breast carcinoma. Journal of Experimental & Clinical Cancer Research, 28(1), 93. https://doi.org/10.1186/1756-9966-28-93
  • Chen, J., (2016). The cell-cycle arrest and apoptotic functions of p53 in tumour initiation and progression. Cold Spring Harbor perspectives in medicine, doi: 10.1101/cshperspect.a026104. https://doi.org/10.1101/cshperspect.a026104
  • Chen, P.S., Wang, C.C., Bortner, C.D., Peng, G.S., Wu, X., Pang, H., Lu, R.B., Gean, P.W., Chuang, D.M. and Hong, J.S., 2007. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience, 149(1), 203–212. https://doi.org/10.1016/j.neuroscience.2007.06.053
  • Choi, J.H., Kwon, H.J., Yoon, B.I., Kim, J.H., Han, S.U., Joo, H.J. and Kim, D.Y., (2001). Expression profile of histone deacetylase 1 in gastric cancer tissues. Cancer science, 92(12), 1300–1304. https://doi.org/10.1111/j.1349-7006.2001.tb02153.x
  • Cress, W.D. and Seto, E., (2000). Histone deacetylases, transcriptional control, and cancer. Journal of cellular physiology, 184(1), 1–16. https://doi.org/10.1002/(SICI)1097-4652(200007)184:1 3.0.CO;2-7
  • De Ruijter, A.J., Van Gennip, A.H., Caron, H.N., Stephan, K.E.M.P. and Van Kuilenburg, A.B., (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemical Journal, 370(3), 737–749. https://doi.org/10.1042/bj20021321
  • Duvic, M., Talpur, R., Ni, X., Zhang, C., Hazarika, P., Kelly, C., Chiao, J.H., Reilly, J.F., Ricker, J.L., Richon, V.M. and Frankel, S.R., (2007). Phase 2 trial of oral vorinostat (suberooylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood, 109(1), 31–39. https://doi.org/10.1182/blood-2006-06-025999
  • Finnin, M.S., Donigian, J.R., Cohen, A. and Richon, V.M., (1999). Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature, 401(6749), 188. https://doi.org/10.1038/43710
  • Forsberg, E.C. and Bresnick, E.H., (2001). Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world. Bioessays, 23(9), 820–830. https://doi.org/10.1002/bies.1117
  • Fraga, M.F., Ballestar, E., Villar-Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C., Ropero, S., Petrie, K. and Iyer, N.G., (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics, 37(4), 391–400. https://doi.org/10.1038/ng1531
  • Fraga, M.F., Ballestar, E., Villar-Garea, A., Boix-Chornet, M., Espada, J., Schotta, G., Bonaldi, T., Haydon, C., Ropero, S., Petrie, K. and Iyer, N.G., (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature genetics, 37(4), 391–400. https://doi.org/10.1038/ng1531
  • Gelmon, K., Tolcher, A., Carducci, M., Reid, G.K., Li, Z., Kalita, A., Callejas, V., Longstreth, J., Besterman, J.M. and Siu, L.L., (2005). Phase I trials of the oral histone deacetylase (HDAC) inhibitor MGCD0103 given either daily or 3x weekly for 14 days every 3 weeks in patients (pts) with advanced solid tumours. Journal of Clinical Oncology, 23(16), 3147–3147. https://doi.org/10.1200/jco.2005.23.16_suppl.3147
  • Georgescu, M.M., (2010). PTEN tumour suppressor network in PI3K-Akt pathway control. Genes & cancer, 1(12), 1170–1177. https://doi.org/10.1177/1947601911407325
  • Glass, C.K. and Rosenfeld, M.G., (2000). The coregulator exchange in transcriptional functions of nuclear receptors. Genes & development, 14(2), 121–141.
  • Glass, C.K. and Rosenfeld, M.G., 2000. The coregulator exchange in transcriptional functions of nuclear receptors. Genes & development, 14(2), 121–141.
  • Gräff, J. and Tsai, L.H., (2013). The potential of HDAC inhibitors as cognitive enhancers. Annual review of pharmacology and toxicology, 53, 311–330. https://doi.org/10.1146/annurev-pharmtox-011112-140216
  • Green, A.L., Zhan, L., Eid, A., Zarbl, H., Guo, G.L. and Richardson, J.R., (2017). Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1. Neuropharmacology, 125, 189–196. https://doi.org/10.1016/j.neuropharm.2017.07.020
  • Green, K.N., Steffan, J.S., Martinez-Coria, H., Sun, X., Schreiber, S.S., Thompson, L.M. and LaFerla, F.M., (2008). Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. Journal of Neuroscience, 28(45), 11500–11510. https://doi.org/10.1523/JNEUROSCI.3203-08.2008
  • Gregersen, R., Lambertsen, K. and Finsen, B., (2000). Microglia and macrophages are the major source of tumour necrosis factor in permanent middle cerebral artery occlusion in mice. Journal of Cerebral Blood Flow & Metabolism, 20(1), 53–65. https://doi.org/10.1097/00004647-200001000-00009
  • Grozinger, C.M., Chao, E.D., Blackwell, H.E., Moazed, D. and Schreiber, S.L., (2001). Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. Journal of Biological Chemistry, 276(42), 38837–38843. https://doi.org/10.1074/jbc.M106779200
  • Gryder, B.E., Sodji, Q.H. and Oyelere, A.K., (2012). Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future medicinal chemistry, 4(4), 505–524. https://doi.org/10.4155/fmc.12.3
  • Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M. and Schreiber, S.L., (2003). Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proceedings of the National Academy of Sciences, 100(8), 4389–4394. https://doi.org/10.1073/pnas.0430973100
  • Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M. and Schreiber, S.L., (2003). Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proceedings of the National Academy of Sciences, 100(8), 4389-4394. https://doi.org/10.1073/pnas.0430973100
  • Hahnen, E., Hauke, J., Tränkle, C., Eyüpoglu, I.Y., Wirth, B. and Blümcke, I., (2008). Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert opinion on investigational drugs, 17(2), 169–184. https://doi.org/10.1517/13543784.17.2.169
  • Halkidou, K., Gaughan, L., Cook, S., Leung, H.Y., Neal, D.E. and Robson, C.N., (2004). Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. The Prostate, 59(2), 177–189. https://doi.org/10.1002/pros.20022
  • Harrison, I.F. and Dexter, D.T., (2013). Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson’s disease? Pharmacology & therapeutics, 140(1), 34–52. https://doi.org/10.1016/j.pharmthera.2013.05.010
  • Iizuka, M. and Smith, M.M., (2003). Functional consequences of histone modifications. Current opinion in genetics & development, 13(2), 154–160. https://doi.org/10.1016/S0959-437X(03)00020-0
  • Ito, K., Barnes, P.J. and Adcock, I.M., (2000). Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1”ö-induced histone H4 acetylation on lysines 8 and 12. Molecular and Cellular Biology, 20(18), 6891–6903. https://doi.org/10.1128/MCB.20.18.6891-6903.2000
  • Jenuwein, T. and Allis, C.D., (2001). Translating the histone code. Science, 293(5532), 1074–1080. https://doi.org/10.1126/science.1063127
  • Johnstone, R.W., (2002). Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature reviews. Drug discovery, 1(4), 287. https://doi.org/10.1038/nrd772
  • Johnstone, R.W., Ruefli, A.A. and Lowe, S.W., (2002). Apoptosis: a link between cancer genetics and chemotherapy. Cell, 108(2), 153–164. https://doi.org/10.1016/S0092-8674(02)00625-6
  • Jones, P.L., Veenstra, J., Gert, C., Wade, P.A., Vermaak, D., Kass, S.U., Landsberger, N., Strouboulis, J. and Wolffe, A.P., (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature genetics, 19(2). https://doi.org/10.1038/561
  • Jose, B., Oniki, Y., Kato, T., Nishino, N., Sumida, Y. and Yoshida, M., (2004). Novel histone deacetylase inhibitors: cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones. Bioorganic & medicinal chemistry letters, 14(21), 5343–5346. https://doi.org/10.1016/j.bmcl.2004.08.016
  • Jose, B., Oniki, Y., Kato, T., Nishino, N., Sumida, Y. and Yoshida, M., (2004). Novel histone deacetylase inhibitors: cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones. Bioorganic & medicinal chemistry letters, 14(21), 5343–5346. https://doi.org/10.1016/j.bmcl.2004.08.016
  • Joseph, J., SIDERIS, M.L., Polly, M.A.K., LORIMER, D.D., MCINTOSH, B. and CLARK, J.M., (2000). Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochemical Journal, 350(1), 199–205. https://doi.org/10.1042/bj3500199
  • Juan, L.J., Shia, W.J., Chen, M.H., Yang, W.M., Seto, E., Lin, Y.S. and Wu, C.W., (2000). Histone deacetylases specifically down-regulate p53-dependent gene activation. Journal of Biological Chemistry, 275(27), 20436–20443. https://doi.org/10.1074/jbc.M000202200
  • Kim D., Frank C. L., Dobbin M. M., Tsunemoto R. K., Tu W., Peng P. L., Guan J. S., Lee B. H., Moy L. Y., Giusti P., Broodie N., Mazitschek R., Delalle I., Haggarty S. J., Neve R. L., Lu Y., and Tsai L. H. (2008) Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803–817. https://doi.org/10.1016/j.neuron.2008.10.015
  • Kim, D., Frank, C.L., Dobbin, M.M., Tsunemoto, R.K., Tu, W., Peng, P.L., Guan, J.S., Lee, B.H., Moy, L.Y., Giusti, P. and Broodie, N., (2008). Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron, 60(5), 803–817. https://doi.org/10.1016/j.neuron.2008.10.015
  • Kim, H.J., Rowe, M., Ren, M., Hong, J.S., Chen, P.S. and Chuang, D.M., (2007). Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. Journal of Pharmacology and Experimental Therapeutics, 321(3), 892–901. https://doi.org/10.1124/jpet.107.120188
  • Kim, M.S., Kwon, H.J., You, M.L., Baek, J.H., Jang, J.E., Sae-Won, L., Moon, E.J., Hae-Sun, K., Seok-Ki, L., Chung, H.Y. and Kim, C.W., (2001). Histone deacetylases induce angiogenesis by negative regulation of tumour suppressor genes. Nature medicine, 7(4), 437. https://doi.org/10.1038/86507
  • Kornberg, R.D. and Lorch, Y., (1999). Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell, 98(3), 285–294. https://doi.org/10.1016/S0092-8674(00)81958-3
  • Kuzmichev, A., Margueron, R., Vaquero, A., Preissner, T.S., Scher, M., Kirmizis, A., Ouyang, X., Brockdorff, N., Abate-Shen, C., Farnham, P. and Reinberg, D., (2005). Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proceedings of the National Academy of Sciences of the United States of America, 102(6), 1859–1864. https://doi.org/10.1073/pnas.0409875102
  • Leoni, F., Fossati, G., Lewis, E.C., Lee, J.K., Porro, G., Pagani, P., Modena, D., Moras, M.L., Pozzi, P., Reznikov, L.L. and Siegmund, B., (2005). The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Molecular medicine, 11(1–12), 1. https://doi.org/10.2119/2006-00005.Dinarello
  • Leventhal, L., Tran, A. and Gallager, I., (2008). The histone deacetylase inhibitor EVP-0334 is pro-cognitive in mice.
  • Li, J., Qian, C., Zhou, Q., Li, J., Li, K. and Yi, P., 2017. BEBT-908: A novel potent PI3K/HDAC inhibitor against diffuse large B-cell lymphoma. Biochemical and Biophysical Research Communications, 491(4), 939–945. https://doi.org/10.1016/j.bbrc.2017.07.139
  • Li, S.H. and Li, X.J., (2004). Huntingtin–protein interactions and the pathogenesis of Huntington’s disease. TRENDS in Genetics, 20(3), 146–154. https://doi.org/10.1016/j.tig.2004.01.008
  • Lin, R.J., Sternsdorf, T., Tini, M. and Evans, R.M., (2001). Transcriptional regulation in acute promyelocytic leukemia. Oncogene, 20(49), 7204. https://doi.org/10.1038/sj.onc.1204853
  • Lincoln, D.T., Ali, E.E., Tonissen, K.F. and Clarke, F.M., (2003). The thioredoxinthioredoxin reductase system: over-expression in human cancer. Anticancer research, 23(3B), 2425–2433.
  • Liu, T., Kapustin, G. and Etzkorn, F.A., (2007). Design and synthesis of a potent histone deacetylase inhibitor. Journal of medicinal chemistry, 50(9), 2003–2006. https://doi.org/10.1021/jm061082q
  • Lo, E.H., Dalkara, T. and Moskowitz, M.A., (2003). Mechanisms, challenges and opportunities in stroke. Nature reviews. Neuroscience, 4(5), 399. https://doi.org/10.1038/nrn1106
  • Mahon, P.C., Hirota, K. and Semenza, G.L., (2001). FIH-1: a novel protein that interacts with HIF-1 and VHL to mediate repression of HIF-1 transcriptional activity. Genes & development, 15(20), 2675–2686. https://doi.org/10.1101/gad.924501
  • Marks, P.A. and Breslow, R., (2007). Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature biotechnology, 25(1), 84. https://doi.org/10.1038/nbt1272
  • Marks, P.A., (2006). Thioredoxin in cancer—role of histone deacetylase inhibitors. In Seminars in cancer biology. 16(6), 436–443. https://doi.org/10.1016/j.semcancer.2006.09.005
  • Marks, P.A., (2010). The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert opinion on investigational drugs, 19(9), 1049–1066. https://doi.org/10.1517/13543784.2010.510514
  • Marks, P.A., Richon, V.M., Miller, T. and Kelly, W.K., (2004). Histone deacetylase inhibitors. Advances in cancer research, 91, 137–168. https://doi.org/10.1016/S0065-230X(04)91004-4
  • Marson, C.M., Mahadevan, T., Dines, J., Sengmany, S., Morrell, J.M., Alao, J.P., Joel, S.P., Vigushin, D.M. and Coombes, R.C., (2007). Structure–activity relationships of aryloxyalkanoic acid hydroxyamides as potent inhibitors of histone deacetylase. Bioorganic & medicinal chemistry letters, 17(1), 136–141. https://doi.org/10.1016/j.bmcl.2006.09.085
  • Mazure, N.M., (2006). Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature, 441(7092), 437. https://doi.org/10.1038/nature04871
  • Mucke, L. and Selkoe, D.J., (2012). Neurotoxicity of amyloid -protein: synaptic and network dysfunction. Cold Spring Harbor perspectives in medicine, 2(7), 1–18. https://doi.org/10.1101/cshperspect.a006338
  • Nakayama, J.I., Rice, J.C., Strahl, B.D., Allis, C.D. and Grewal, S.I., (2001). Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science, 292(5514), 110–113. https://doi.org/10.1126/science.1060118
  • Nan, X., Ng, H.H., Johnson, C.A. and Laherty, C.D., (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature, 393(6683), 386. https://doi.org/10.1038/30764
  • Naseri, M.H., Mahdavi, M., Davoodi, J., Tackallou, S.H., Goudarzvand, M. and Neishabouri, S.H., (2015). Up regulation of Bax and down regulation of Bcl2 during 3-NC mediated apoptosis in human cancer cells. Cancer cell international, 15(1), 55. https://doi.org/10.1186/s12935-015-0204-2
  • Nowak, S.J. and Corces, V.G., (2004). Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. TRENDS in Genetics, 20(4), 214–220. https://doi.org/10.1016/j.tig.2004.02.007
  • Özda, H., Teschendorff, A.E., Ahmed, A.A., Hyland, S.J., Blenkiron, C., Bobrow, L., Veerakumarasivam, A., Burtt, G., Subkhankulova, T., Arends, M.J. and Collins, V.P.,(2006). Differential expression of selected histone modifier genes in human solid cancers. BMC genomics, 7(1), 90. https://doi.org/10.1186/1471-2164-7-90
  • Park, B.J., Cha, M.K. and Kim, I.H., (2014). Thioredoxin 1 as a serum marker for breast cancer and its use in combination with CEA or CA15-3 for improving the sensitivity of breast cancer diagnoses. BMC research notes, 7(1), 7. https://doi.org/10.1186/1756-0500-7-7
  • Pidugu, V.R., Yarla, N.S., Bishayee, A., Kalle, A.M. and Satya, A.K., 2017. Novel histone deacetylase 8-selective inhibitor 1, 3, 4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells. Apoptosis, 1–10. https://doi.org/10.1007/s10495-017-1410-2
  • Pidugu, V.R., Yarla, N.S., Pedada, S.R., Kalle, A.M. and Satya, A.K., (2016). Design and synthesis of novel HDAC8 inhibitory 2, 5-disubstituted-1, 3, 4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity. Bioorganic & medicinal chemistry, 24(21), 5611–5617. https://doi.org/10.1016/j.bmc.2016.09.022
  • Polo, S.E. and Almouzni, G., (2005). Histone metabolic pathways and chromatin assembly factors as proliferation markers. Cancer letters, 220(1), 1–9 https://doi.org/10.1016/j.canlet.2004.08.024
  • Qian, D.Z., Kachhap, S.K., Collis, S.J., Verheul, H.M., Carducci, M.A., Atadja, P. and Pili, R., (2006). Class II histone deacetylases are associated with VHLindependent regulation of hypoxia-inducible factor 1. Cancer research, 66(17), 8814–8821. https://doi.org/10.1158/0008-5472.CAN-05-4598
  • Rasheed, W.K., Johnstone, R.W. and Prince, H.M., (2007). Histone deacetylase inhibitors in cancer therapy. Expert opinion on investigational drugs, 16(5), 659–678. https://doi.org/10.1517/13543784.16.5.659
  • Richon, V.M., Emiliani, S., Verdin, E., Webb, Y., Breslow, R., Rifkind, R.A. and Marks, P.A., (1998). A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proceedings of the National Academy of Sciences, 95(6), 3003–3007. https://doi.org/10.1073/pnas.95.6.3003
  • Richon, V.M., Webb, Y., Merger, R., Sheppard, T., Jursic, B., Ngo, L., Civoli, F., Breslow, R., Rifkind, R.A. and Marks, P.A., (1996). Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proceedings of the National Academy of Sciences, 93(12), 5705–5708. https://doi.org/10.1073/pnas.93.12.5705
  • Rikiishi, H., (2011). Autophagic and apoptotic effects of HDAC inhibitors on cancer cells. Journal of Biomedicine and Biotechnology, 2011, 1–9. https://doi.org/10.1155/2011/830260
  • Robertson, K.D., Ait-Si-Ali, S., Yokochi, T., Wade, P.A., Jones, P.L. and Wolffe, A.P., (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature genetics, 25(3), 338. https://doi.org/10.1038/77124
  • Roth, S.Y., Denu, J.M. and Allis, C.D., (2001). Histone acetyltransferases. Annual review of biochemistry, 70(1), 81–120. https://doi.org/10.1146/annurev.biochem.70.1.81
  • Sadri-Vakili, G. and Cha, J.H.J., (2006). Histone deacetylase inhibitors: a novel therapeutic approach to Huntington’s disease (complex mechanism of neuronal death). Current Alzheimer Research, 3(4), 403–408. https://doi.org/10.2174/156720506778249407
  • Solinas, G., Germano, G., Mantovani, A. and Allavena, P., (2009). Tumourassociated macrophages (TAM) as major players of the cancer-related inflammation. Journal of leukocyte biology, 86(5), 1065–1073. https://doi.org/10.1189/jlb.0609385
  • Somoza, J.R., Skene, R.J., Katz, B.A., Mol, C., Ho, J.D., Jennings, A.J., Luong, C., Arvai, A., Buggy, J.J., Chi, E. and Tang, J., (2004). Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure, 12(7), 1325–1334. https://doi.org/10.1016/j.str.2004.04.012
  • Song, C., Kanthasamy, A., Anantharam, V., Sun, F. and Kanthasamy, A.G., (2010). Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Molecular pharmacology, 77(4), 621–632. https://doi.org/10.1124/mol.109.062174
  • Song, C., Kanthasamy, A., Jin, H., Anantharam, V. and Kanthasamy, A.G., (2011). Paraquat induces epigenetic changes by promoting histone acetylation in cell culture models of dopaminergic degeneration. Neurotoxicology, 32(5), 586–595. https://doi.org/10.1016/j.neuro.2011.05.018
  • Strahl, B.D. and Allis, C.D., (2000). The language of covalent histone modifications. Nature, 403(6765), 41. https://doi.org/10.1038/47412
  • Stridh, P., (2010). Inheritance of autoimmune neuroinflammation. Institutionen för klinisk neurovetenskap/Department of Clinical Neuroscience.
  • Tanny, J.C., Erdjument-Bromage, H., Tempst, P. and Allis, C.D., (2007). Ubiquitylation of histone H2B controls RNA polymerase II transcription elongation independently of histone H3 methylation. Genes & development, 21(7), 835–847. https://doi.org/10.1101/gad.1516207
  • Timmermann, S., Lehrmann, H., Polesskaya, A. and Harel-Bellan, A., (2001). Histone acetylation and disease. Cellular and Molecular Life Sciences, 58(5), 728–736. https://doi.org/10.1007/PL00000896
  • Verdel, A. and Khochbin, S., (1999). Identification of a new family of higher eukaryotic histone deacetylases coordinate expression of differentiationdependent chromatin modifiers. Journal of Biological Chemistry, 274(4), 2440–2445. https://doi.org/10.1074/jbc.274.4.2440
  • Vidanes, G.M., Bonilla, C.Y. and Toczyski, D.P., (2005). Complicated tails: histone modifications and the DNA damage response. Cell, 121(7), 973–976. https://doi.org/10.1016/j.cell.2005.06.013
  • Wade, P.A., (2001). Transcriptional control at regulatory checkpoints by histone deacetylases: molecular connections between cancer and chromatin. Human molecular genetics, 10(7), 693–698. https://doi.org/10.1093/hmg/10.7.693
  • Wei, Z., Shan, Y., Tao, L., Liu, Y., Zhu, Z., Liu, Z., Wu, Y., Chen, W., Wang, A. and Lu, Y., (2017). Diallyl Trisulfides, a natural histone deacetylase inhibitor, attenuate HIF1 synthesis and decreases Breast Cancer Metastasis. Molecular Carcinogenesis. https://doi.org/10.1002/mc.22686
  • Wilson, A.J., Byun, D.S., Popova, N., Murray, L.B., L’Italien, K., Sowa, Y., Arango, D., Velcich, A., Augenlicht, L.H. and Mariadason, J.M., (2006). Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. Journal of Biological Chemistry, 281(19), 13548–13558. https://doi.org/10.1074/jbc.M510023200
  • Xu, K., Dai, X.L., Huang, H.C. and Jiang, Z.F., (2011). Targeting HDACs: a promising therapy for Alzheimer’s disease. Oxidative medicine and cellular longevity, 2011. https://doi.org/10.1155/2011/143269
  • Xu, W.S., Parmigiani, R.B. and Marks, P.A., (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 26(37), 5541. https://doi.org/10.1038/sj.onc.1210620
  • Xu, W.S., Parmigiani, R.B. and Marks, P.A., (2007). Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 26(37), 5541. https://doi.org/10.1038/sj.onc.1210620
  • Yasui, W., Oue, N., Ono, S., Mitani, Y., Ito, R. and Nakayama, H., (2003). Histone acetylation and gastrointestinal carcinogenesis. Annals of the New York Academy of Sciences, 983(1), 220–231. https://doi.org/10.1111/j.1749-6632.2003.tb05977.x
  • Yazbeck, V.Y. and Grant, S., (2015). Romidepsin for the treatment of non- Hodgkin’s lymphoma. Expert opinion on investigational drugs, 24(7), 965–979. https://doi.org/10.1517/13543784.2015.1041586
  • Yeung, F., Hoberg, J.E., Ramsey, C.S., Keller, M.D., Jones, D.R., Frye, R.A. and Mayo, M.W., (2004). Modulation of NFBdependent transcription and cell survival by the SIRT1 deacetylase. The EMBO journal, 23(12), 2369–2380. https://doi.org/10.1038/sj.emboj.7600244
  • Zhang, M.F., Zhang, Z.Y., Fu, J., Yang, Y.F. and Yun, J.P., (2009). Correlation between expression of p53, p21/WAF1, and MDM2 proteins and their prognostic significance in primary hepatocellular carcinoma. Journal of translational medicine, 7(1), 110. https://doi.org/10.1186/1479-5876-7-110
  • Zhang, X.D., Gillespie, S.K., Borrow, J.M. and Hersey, P., (2004). The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells. Molecular cancer therapeutics, 3(4), 425–435.
  • Zhang, Y. and Reinberg, D., (2001). Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes & development, 15(18), 2343–2360. https://doi.org/10.1101/gad.927301
  • Zhang, Z., Yamashita, H., Toyama, T., Sugiura, H., Ando, Y., Mita, K., Hamaguchi, M., Hara, Y., Kobayashi, S. and Iwase, H., (2005). Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast cancer research and treatment, 94(1), 11–16. https://doi.org/10.1007/s10549-005-6001-1
  • Zhang, Z., Yamashita, H., Toyama, T., Sugiura, H., Omoto, Y., Ando, Y., Mita, K., Hamaguchi, M., Hayashi, S.I. and Iwase, H., (2004). HDAC6 expression is correlated with better survival in breast cancer. Clinical Cancer Research, 10(20), 6962–6968. https://doi.org/10.1158/1078-0432.CCR-04-0455
  • Zhao, Y., Tan, J., Zhuang, L., Jiang, X., Liu, E.T. and Yu, Q., (2005). Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proceedings of the National Academy of Sciences of the United States of America, 102(44), 16090–16095. https://doi.org/10.1073/pnas.0505585102
  • Zhu, P., Martin, E., Mengwasser, J., Schlag, P., Janssen, K.P. and Göttlicher, M., (2004). Induction of HDAC2 expression upon loss of APC in colorectal tumourigenesis. Cancer cell, 5(5), 455–463. https://doi.org/10.1016/S1535-6108(04)00114-X