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World J Biol Chem. May 26, 2010; 1(5): 55-61
Published online May 26, 2010. doi: 10.4331/WJBC.v1.i5.55
Deacetylase inhibitors - focus on non-histone targets and effects
Matthias Ocker
Matthias Ocker, Institute for Surgical Research, Philipps University Marburg, Baldingerstrasse, 35033 Marburg, Germany
Author contributions: Ocker M solely contributed to this paper.
Supported by Supported by a Research Grant of the University Medical Center Giessen and Marburg
Correspondence to: Matthias Ocker, MD, Professor of Medicine, Director, Institute for Surgical Research, Philipps University Marburg, Baldingerstrasse, 35033 Marburg, Germany. ocker@staff.uni-marburg.de
Telephone: +49-6421-5868930 Fax: +49-6421-5868926
Received: April 6, 2010
Revised: April 23, 2010
Accepted: April 30, 2010
Published online: May 26, 2010


Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases, including cancer. The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes, by interfering with the acetylation status of nuclear histone proteins, hence the name histone deacetylase inhibitors was coined. Yet, this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation, survival and cell death induction.

Key Words: Epigenetics, Histone deacetylase inhibitors, Histone code, Posttranslational modifications, Unfolded protein response

Citation: Ocker M. Deacetylase inhibitors - focus on non-histone targets and effects. World J Biol Chem 2010; 1(5): 55-61

Histones were historically viewed as structural proteins allowing the chromatin to be folded into the nucleus. The discovery of post-translational modifications like methylation and acetylation in the 1960s proposed functions in addition to mere scaffolding of DNA[1,2]. Acetylation and deacetylation are achieved by two groups of highly conserved enzyme families termed histone acetyl transferases (HAT) and histone deacetylases (HDAC) because histones were their first identified targets.


HAT comprise an evolutionary highly conserved group of enzymes. The first HAT was identified in yeast as Hat1[3] and so far more than 30 different HATs with known substrate specificity have been described in mammals[4-6]. Two general classes of HATs have been described: A-type HATs which mainly regulate transcriptional processes and show a nuclear localization and B-type HATs which are predominantly expressed in the cytoplasm[7,8].

HATs usually transfer acetyl groups to ε-amino groups of lysine residues in basic core histone proteins which alters the DNA-histone or DNA-protein interaction due to altered electrochemical properties between positively charged histones and the negatively charged DNA backbone[9,10]. This and additional steric effects of acetylated lysine residues render the chromatin in an “open” conformation and thus facilitates the binding of transcription factors[11]. These post-translational modifications were viewed as a key regulatory process for gene transcription and hence the term “histone code” was coined[12-14]. As the effect of HAT and HDAC are rather broad, the concept of a code that specifically regulates target gene expression has been weakened and data from gene array experiments show that only 2%-10% of all genes are regulated by this mechanism[15,16].


Today, four different classes with at least 18 subtypes of HDAC have been described[11,17,18]: class I (Rpd3-like) represents the ubiquitously expressed zinc-dependent isotypes HDAC1, 2, 3 and 8. These isotypes are usually localized in the nucleus and act as transcriptional corepressors. Class II (Had1-like), consisting of HDAC4, 5, 6, 7, 9 and 10, shows a tissue-specific distribution and is localized in the nucleus and the cytoplasm, although histone proteins also seem to represent the major target. Class III (sirtuins) represents the zinc-independent enzymes SIRT1 to SIRT7 that have been associated with cell proliferation and cell cycle control. HDAC11 has homology to the class I HDACs but shows a more restricted tissue distribution and also has a cytoplasmic localization and is therefore considered a distinct 4th class of HDAC[19,20]. Interestingly, HDAC6 and HDAC10 (also designated as class IIb) have two catalytic sites and show a mainly cytoplasmic localization.

The overexpression of HDAC isoenzymes has also been linked to a variety of human cancer diseases[17], e.g. HDAC1 in gastric[21] or breast cancer[22], HDAC3 in colon cancer[23] and HDAC6 also in breast cancer[24], without a complete understanding of whether this overexpression is a precondition of the malignant phenotype or a consequence of a general process of gene dysregulation. Little is known about the different functions of the HDAC isotypes in the investigated tissues.


Several chemically distinct histone deacetylase inhibitors (HDACi) have been developed and are currently undergoing clinical trials[11,18]. So far, only the hydroxamate vorinostat [suberoylanilide hydroxamic acid (SAHA)] has been approved for clinical use in patients with cutaneous T-cell lymphoma[25]. Generally, hydroxamates like vorinostat, panobinostat (LBH589), trichostatin A or belinostat (PXD101) are unspecific HDACi with activity against classes I, IIa, IIb and IV of HDAC[26]. Other compounds specifically inhibit class I HDACs, e.g. the benzamide MS-275 or the cyclic tetrapeptide depsipeptide, or class I and IIa HDACs, e.g. the short-chain fatty acids valproic acid or butyrate[26,27]. As the various roles of HDAC isotypes are still unclear it is also under debate whether isotype or class specific HDACi should be preferred over the broad-spectrum inhibitors. The selectivity of the compounds has also been demonstrated by a divergent pattern of acetylation of α-tubulin, histone H3 and histone H4, which indicates that these proteins may not be suitable biomarkers for the clinical use of all HDACi[26,28]. Except for the HDAC6-specific compound tubacin[29], all classes of HDACi lead to a G1/S-phase arrest of the cell cycle which is commonly associated with an increased expression of the endogenous cyclin-dependent kinase inhibitor p21cip1/waf1[17,30,31]. Although p21cip1/waf1 has been shown to be a transcriptional target of p53[32-34], HDACi mediated induction of p21cip1/waf1 can occur by p53-dependent and -independent mechanisms[35,36], and our own results showed that the anti-tumor effect of HDACi is independent of p53 but is facilitated by the absence or inhibition of p21cip1/waf1[37-39].


Today, only the pan-deacetylase inhibitor SAHA (vorinostat) has been approved for clinical use in cutaneous T-cell lymphoma by the FDA[40]. Other HDACi are currently undergoing intensive clinical investigations in various human tumor entities, with most trials focusing on hematologic indications such as acute or chronic leukemias, myelodysplastic syndrome or lymphomas[41,42]. Although the currently available results are promising with regard to their overall response rates (usually around 30%), no long-term experience with these compounds has been reported. From a clinical point of view, it is also unclear whether the more specific class I and II inhibitors like MS-275 or the pan-deacetylase inhibitors like SAHA or panobinostat provide better treatment responses. Interestingly, the toxicity profiles of HDACi are comparable, mainly gastrointestinal side effects (diarrhea), myelosuppression and cardiac QT prolongation, over the different types of HDACi. Most HDACi have a rather short half-life in plasma (2-8 h) and undergo hepatic metabolization with subsequent intestinal excretion[43-48]. Yet, the effect of HDACi on histone H3 acetylation in peripheral blood mononuclear cells is stable for approximately 10 h after oral dosing[43]. This was initially considered a suitable biomarker for the efficacy of HDACi in tumors but several studies were unable to establish a correlation between peripheral H3 acetylation and tumor target effects, probably due to the numerous non-histone targets of HDACi to be discussed later[41,42].


HDACi have been demonstrated to be potent inducers of apoptotic cell death in human tumor cells and also show strong effects in various animal models and in clinical trials. Interestingly, these compounds show a high specificity for tumor cells with a so far unknown mechanism of action. This observation (along with the low number of genes affected by HDACi) is in contrast to the established view of these compounds as general modulators of chromatin and transcription.

It was demonstrated that HDACi induce apoptotic cell death by activating both, the extrinsic (TRAIL-mediated) and the intrinsic (mitochondria-related) pathway of apoptosis, e.g. by upregulation of death receptors (hDR4, hDR5) or suppression of bcl-2 family proteins[38,49-56]. Although most of these effects are also mediated by the transcriptional control of hyperacetylated p53 or histones[57], other pro-apoptotic effects of HDACi, e.g. the generation of reactive oxygen species, also contribute to this effect[58-60] and are currently not understood at the molecular level.

Additional anti-cancer effects of HDACi include a synergistic enhancement of other cytostatic agents, including gemcitabine[61], 5-fluorouracil and irinotecan[62], but also targeted agents like imatinib[63], bortezomib[64], sorafenib[65,66] or antibodies like trastuzumab[67]. In vivo, HDACi also inhibit angiogenesis by decreasing the expression of pro-angiogenic factors like vascular endothelial growth factor and hypoxia inducible factor-1α (HIF-1α) or inducing endothelial cell death[39,68-71]. These effects are also closely associated with an inhibition of invasion and metastasis by HDACi[72,73].

HDACi have also been associated with a variety of immunomodulatory effects, e.g. by hyperacetylation of STAT1, STAT3 or NF-κB and a subsequent modulation of downstream inflammatory pathways[74-80]. Besides these gene regulatory effects, HDACi can also exert immunologic effects by affecting the acetylation status of regular cellular proteins which are then presented via major histocompatibility complexes I and II.


Post-translational modifications of proteins, including phosphorylation, ubiquitination, methylation, acetylation and other processes, are important regulators of protein function and homeostasis in eukaryotic cells[81]. Although protein acetylation at lysine residues was discovered in the 1960s[2], analysis of the acetylome was hampered due to technical reasons[82,83]. Two recent studies have now provided new insights into the acetylome as well as the effects of different HDACi, and showed that various cellular networks, e.g. RNA splicing, DNA damage repair, cell cycle control, nuclear transport, actin remodeling, ribosome and chaperone function are intensively affected by changes in protein acetylation[84,85] which were previously postulated on a theoretical basis[86]. These studies also showed that > 20% of mitochondrial proteins are acetylated, which provides a functional connection between the localization of the class III HDAC to mitochondria[87,88] and the effect of HDACi on the mitochondrial transmembrane potential (ΔΨm)[37,38,61]. Analysis of the acetylome revealed for the first time that this mechanism of regulation is as complex as the known pathways of protein phosphorylation, although no clear signaling cascades have be established so far[10,82].

Besides the already discussed effects via acetylation of transcription factors like STAT1, STAT3, Nf-κB and others[10], HAT and HDAC enzymes are also part of multi-enzyme complexes involved in post-transcriptional pre-mRNA processing, mRNA stability and translation, e.g. by interfering with DNA methyltransferases[89,90]. Recently, an influence of HDACi on miRNA expression profiles has been described[91].

Protein acetylation contributes to the protein turnover via proteasomal and non-proteasomal pathways[92]. Interestingly, acetylation can either prevent ubiquitination and subsequent proteasomal degradation (e.g. for p53 or p73) or enhance the degradation of tagged proteins (e.g. HIF-1α or pRb)[93,94]. The stabilization of proteins by acetylation has been shown to involve sites also necessary for the effect of ubiquitin ligases, e.g. at C-terminal lysine residues of p53[95]. In contrast, HDACi have also been shown to induce the expression of E2 and E3 ubiquitin conjugases and ligases Ubc8 and RLIM that can then lead to enhanced ubiquitination of target proteins[96,97]. Although these contradicting phenomena are not completely solved, most reports show a synergistic effect of HDACi with a proteasome inhibitor[98-101]. The tolerability of these combination therapies still needs to be investigated in clinical trials.


The correct folding of proteins by chaperones is a crucial step for homeostasis and maintenance of cellular physiology. Chaperones like heat shock proteins (Hsp) are also a direct target of deacetylases[102]. Hyperacetylation inactivates chaperone function, e.g. of Hsp90, which then leads to misfolding and degradation of Hsp90 target genes[103,104]. This pathway has been demonstrated, among many others, for the oncogene bcr-abl[105] and the receptor tyrosine kinase Erb2[67].

Chaperone function also plays a critical role in the activation of the unfolded protein response (UPR). This pathway is part of a cellular stress response when physiologic conditions of protein folding at the endoplasmic reticulum (ER) are disturbed[106], e.g. after nutrient deprivation or by hyperacetylation of lysine residues[107]. ER stress and UPR can lead to apoptotic cell death by activation of caspase 4/12[108-110] and inhibition of p53[111]. Vorinostat was recently shown to inhibit the function of the chaperone protein GRP78 which leads to activation of PERK and execution of apoptosis[112]. Interestingly, our own data with the pan-deacetylase inhibitor panobinostat (LBH589) also shows that apoptotic cell death is not achieved via the canonical intrinsic or extrinsic pathways but by the contribution of the UPR with activation of caspase 12[39]. However, it is unclear if this mechanism is activated via hyperacetylation of Hsp chaperones or by so far unknown proteins that might e.g. regulate protein export from the ER or the Golgi apparatus. ER stress and the UPR can also activate autophagy as another means of clearing misfolded proteins, which can also lead to cellular death pathways[113]. Several HDACi have been shown to induce autophagic cell death[114-117] and interestingly, vorinostat could also abrogate the survival mechanism of autophagy[118].


Deacetylase inhibitors interfere with a plethora of cellular proteins that are involved in regulating central processes of cellular homeostasis and survival. In cancer cells, the interference with these pathways opens new ways for therapy and the current pharmacologic inhibitors of deacetylases are clearly potent agents with more effects than only chromatin remodeling. Further studies are thus urgently warranted to depict the above described pathways and mechanisms more clearly to gain a better understanding of the high tumor cell specificity of these compounds.


Peer reviewers: Sinisa Dovat, MD, DSc, Assistant Professor, Director, Molecular Oncology Research, University of Wisconsin - Madison, Department of Pediatrics, Division of Pediatric Hematology/Oncology, 4137 Wisconsin Institutes for Medical Research, 1111 Highland Ave., Madison, WI 53705-2275, United States; Jianping Ye, MD, Professor of Molecular Biology, Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, United States

S- Editor Cheng JX L- Editor Webster JR E- Editor Zheng XM

1.  Phillips DM. The presence of acetyl groups of histones. Biochem J. 1963;87:258-263.  [PubMed]  [DOI]
2.  Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role in the regulation of rna synthesis. Proc Natl Acad Sci USA. 1964;51:786-794.  [PubMed]  [DOI]
3.  Kleff S, Andrulis ED, Anderson CW, Sternglanz R. Identification of a gene encoding a yeast histone H4 acetyltransferase. J Biol Chem. 1995;270:24674-24677.  [PubMed]  [DOI]
4.  Yang XJ. Lysine acetylation and the bromodomain: a new partnership for signaling. Bioessays. 2004;26:1076-1087.  [PubMed]  [DOI]
5.  Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 2004;32:959-976.  [PubMed]  [DOI]
6.  Kimura A, Matsubara K, Horikoshi M. A decade of histone acetylation: marking eukaryotic chromosomes with specific codes. J Biochem. 2005;138:647-662.  [PubMed]  [DOI]
7.  Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem. 2001;70:81-120.  [PubMed]  [DOI]
8.  Marmorstein R, Roth SY. Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev. 2001;11:155-161.  [PubMed]  [DOI]
9.  Santos-Rosa H, Caldas C. Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer. 2005;41:2381-2402.  [PubMed]  [DOI]
10.  Spange S, Wagner T, Heinzel T, Krämer OH. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009;41:185-198.  [PubMed]  [DOI]
11.  Schneider-Stock R, Ocker M. Epigenetic therapy in cancer: molecular background and clinical development of histone deacetylase and DNA methyltransferase inhibitors. IDrugs. 2007;10:557-561.  [PubMed]  [DOI]
12.  de la Cruz X, Lois S, Sánchez-Molina S, Martínez-Balbás MA. Do protein motifs read the histone code? Bioessays. 2005;27:164-175.  [PubMed]  [DOI]
13.  Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41-45.  [PubMed]  [DOI]
14.  Fischle W, Wang Y, Allis CD. Binary switches and modification cassettes in histone biology and beyond. Nature. 2003;425:475-479.  [PubMed]  [DOI]
15.  Daly K, Shirazi-Beechey SP. Microarray analysis of butyrate regulated genes in colonic epithelial cells. DNA Cell Biol. 2006;25:49-62.  [PubMed]  [DOI]
16.  Gray SG, Qian CN, Furge K, Guo X, Teh BT. Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol. 2004;24:773-795.  [PubMed]  [DOI]
17.  Ocker M, Schneider-Stock R. Histone deacetylase inhibitors: signalling towards p21cip1/waf1. Int J Biochem Cell Biol. 2007;39:1367-1374.  [PubMed]  [DOI]
18.  Marks PA, Xu WS. Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem. 2009;107:600-608.  [PubMed]  [DOI]
19.  Lawless MW, Norris S, O'Byrne KJ, Gray SG. Targeting histone deacetylases for the treatment of disease. J Cell Mol Med. 2009;13:826-852.  [PubMed]  [DOI]
20.  Yang XJ, Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol. 2008;9:206-218.  [PubMed]  [DOI]
21.  Choi JH, Kwon HJ, Yoon BI, Kim JH, Han SU, Joo HJ, Kim DY. Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn J Cancer Res. 2001;92:1300-1304.  [PubMed]  [DOI]
22.  Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Hara Y, Kobayashi S, Iwase H. Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast*. Breast Cancer Res Treat. 2005;94:11-16.  [PubMed]  [DOI]
23.  Wilson AJ, Byun DS, Popova N, Murray LB, L'Italien K, Sowa Y, Arango D, Velcich A, Augenlicht LH, Mariadason JM. 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. 2006;281:13548-13558.  [PubMed]  [DOI]
24.  Zhang Z, Yamashita H, Toyama T, Sugiura H, Omoto Y, Ando Y, Mita K, Hamaguchi M, Hayashi S, Iwase H. HDAC6 expression is correlated with better survival in breast cancer. Clin Cancer Res. 2004;10:6962-6968.  [PubMed]  [DOI]
25.  Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007;25:84-90.  [PubMed]  [DOI]
26.  Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5:769-784.  [PubMed]  [DOI]
27.  Hu E, Dul E, Sung CM, Chen Z, Kirkpatrick R, Zhang GF, Johanson K, Liu R, Lago A, Hofmann G. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther. 2003;307:720-728.  [PubMed]  [DOI]
28.  Blagosklonny MV, Robey R, Sackett DL, Du L, Traganos F, Darzynkiewicz Z, Fojo T, Bates SE. Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol Cancer Ther. 2002;1:937-941.  [PubMed]  [DOI]
29.  Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA. 2003;100:4389-4394.  [PubMed]  [DOI]
30.  Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 2000;97:10014-10019.  [PubMed]  [DOI]
31.  Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA. 2004;101:1241-1246.  [PubMed]  [DOI]
32.  el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817-825.  [PubMed]  [DOI]
33.  Gartel AL, Radhakrishnan SK, Serfas MS, Kwon YH, Tyner AL. A novel p21WAF1/CIP1 transcript is highly dependent on p53 for its basal expression in mouse tissues. Oncogene. 2004;23:8154-8157.  [PubMed]  [DOI]
34.  Gartel AL, Tyner AL. Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res. 1999;246:280-289.  [PubMed]  [DOI]
35.  Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T. Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002;21:2672-2681.  [PubMed]  [DOI]
36.  Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, Tischler J, Chiocca S, Suske G, Rotheneder H, Wintersberger E. The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol Cell Biol. 2003;23:2669-2679.  [PubMed]  [DOI]
37.  Gahr S, Peter G, Wissniowski TT, Hahn EG, Herold C, Ocker M. The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines. Oncol Rep. 2008;20:1249-1256.  [PubMed]  [DOI]
38.  Zopf S, Neureiter D, Bouralexis S, Abt T, Glaser KB, Okamoto K, Ganslmayer M, Hahn EG, Herold C, Ocker M. Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo. Int J Oncol. 2007;31:1391-1402.  [PubMed]  [DOI]
39.  Di Fazio P, Schneider-Stock R, Neureiter D, Okamoto K, Wissniowski T, Gahr S, Quint K, Meissnitzer M, Alinger B, Montalbano R. The pan-deacetylase inhibitor panobinostat inhibits growth of hepatocellular carcinoma models by alternative pathways of apoptosis. Cell Oncol. 2010;32:285-300.  [PubMed]  [DOI]
40.  Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007;12:1247-1252.  [PubMed]  [DOI]
41.  Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009;15:3958-3969.  [PubMed]  [DOI]
42.  Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27:5459-5468.  [PubMed]  [DOI]
43.  Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23:3923-3931.  [PubMed]  [DOI]
44.  Rubin EH, Agrawal NG, Friedman EJ, Scott P, Mazina KE, Sun L, Du L, Ricker JL, Frankel SR, Gottesdiener KM. A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res. 2006;12:7039-7045.  [PubMed]  [DOI]
45.  Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, Brooks R, Piekarz RL, Tucker E, Figg WD. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res. 2002;8:718-728.  [PubMed]  [DOI]
46.  Garcia-Manero G, Assouline S, Cortes J, Estrov Z, Kantarjian H, Yang H, Newsome WM, Miller WH Jr, Rousseau C, Kalita A. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood. 2008;112:981-989.  [PubMed]  [DOI]
47.  Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060-1066.  [PubMed]  [DOI]
48.  Lech-Maranda E, Robak E, Korycka A, Robak T. Depsipeptide (FK228) as a novel histone deacetylase inhibitor: mechanism of action and anticancer activity. Mini Rev Med Chem. 2007;7:1062-1069.  [PubMed]  [DOI]
49.  Fulda S. Modulation of TRAIL-induced apoptosis by HDAC inhibitors. Curr Cancer Drug Targets. 2008;8:132-140.  [PubMed]  [DOI]
50.  Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008;269:7-17.  [PubMed]  [DOI]
51.  Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, Lauer UM, Bitzer M. HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology. 2006;43:425-434.  [PubMed]  [DOI]
52.  Schuchmann M, Schulze-Bergkamen H, Fleischer B, Schattenberg JM, Siebler J, Weinmann A, Teufel A, Wörns M, Fischer T, Strand S. Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. Oncol Rep. 2006;15:227-230.  [PubMed]  [DOI]
53.  Kim HR, Kim EJ, Yang SH, Jeong ET, Park C, Lee JH, Youn MJ, So HS, Park R. Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway? Exp Mol Med. 2006;38:616-624.  [PubMed]  [DOI]
54.  Gillespie S, Borrow J, Zhang XD, Hersey P. Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. Apoptosis. 2006;11:2251-2265.  [PubMed]  [DOI]
55.  Dasmahapatra G, Almenara JA, Grant S. Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. Mol Pharmacol. 2006;69:288-298.  [PubMed]  [DOI]
56.  Marks PA, Jiang X. Histone deacetylase inhibitors in programmed cell death and cancer therapy. Cell Cycle. 2005;4:549-551.  [PubMed]  [DOI]
57.  Xu Y. Regulation of p53 responses by post-translational modifications. Cell Death Differ. 2003;10:400-403.  [PubMed]  [DOI]
58.  Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, Johnstone RW. 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. 2001;98:10833-10838.  [PubMed]  [DOI]
59.  Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, Richon VM. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci USA. 2002;99:11700-11705.  [PubMed]  [DOI]
60.  Ungerstedt JS, Sowa Y, Xu WS, Shao Y, Dokmanovic M, Perez G, Ngo L, Holmgren A, Jiang X, Marks PA. Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2005;102:673-678.  [PubMed]  [DOI]
61.  Gahr S, Ocker M, Ganslmayer M, Zopf S, Okamoto K, Hartl A, Leitner S, Hahn EG, Herold C. The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells. Int J Oncol. 2007;31:567-576.  [PubMed]  [DOI]
62.  Ocker M, Alajati A, Ganslmayer M, Zopf S, Lüders M, Neureiter D, Hahn EG, Schuppan D, Herold C. The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells. J Cancer Res Clin Oncol. 2005;131:385-394.  [PubMed]  [DOI]
63.  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. 2003;101:3236-3239.  [PubMed]  [DOI]
64.  Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood. 2003;102:3765-3774.  [PubMed]  [DOI]
65.  Zhang G, Park MA, Mitchell C, Hamed H, Rahmani M, Martin AP, Curiel DT, Yacoub A, Graf M, Lee R. Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. Clin Cancer Res. 2008;14:5385-5399.  [PubMed]  [DOI]
66.  Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S. Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation. Clin Cancer Res. 2007;13:4280-4290.  [PubMed]  [DOI]
67.  Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther. 2003;2:971-984.  [PubMed]  [DOI]
68.  Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B, Sanni T, Atadja P, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res. 2006;12:634-642.  [PubMed]  [DOI]
69.  Michaelis M, Michaelis UR, Fleming I, Suhan T, Cinatl J, Blaheta RA, Hoffmann K, Kotchetkov R, Busse R, Nau H. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol. 2004;65:520-527.  [PubMed]  [DOI]
70.  Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, Blacher S, Verdin E, Foidart JM, Nusgens BV. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 2002;21:427-436.  [PubMed]  [DOI]
71.  Mottet D, Bellahcène A, Pirotte S, Waltregny D, Deroanne C, Lamour V, Lidereau R, Castronovo V. Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res. 2007;101:1237-1246.  [PubMed]  [DOI]
72.  Klisovic DD, Klisovic MI, Effron D, Liu S, Marcucci G, Katz SE. Depsipeptide inhibits migration of primary and metastatic uveal melanoma cell lines in vitro: a potential strategy for uveal melanoma. Melanoma Res. 2005;15:147-153.  [PubMed]  [DOI]
73.  Coradini D, Zorzet S, Rossin R, Scarlata I, Pellizzaro C, Turrin C, Bello M, Cantoni S, Speranza A, Sava G. Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But. Clin Cancer Res. 2004;10:4822-4830.  [PubMed]  [DOI]
74.  Leng C, Gries M, Ziegler J, Lokshin A, Mascagni P, Lentzsch S, Mapara MY. Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp Hematol. 2006;34:776-787.  [PubMed]  [DOI]
75.  Klampfer L, Huang J, Swaby LA, Augenlicht L. Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem. 2004;279:30358-30368.  [PubMed]  [DOI]
76.  Klampfer L, Huang J, Shirasawa S, Sasazuki T, Augenlicht L. Histone deacetylase inhibitors induce cell death selectively in cells that harbor activated kRasV12: The role of signal transducers and activators of transcription 1 and p21. Cancer Res. 2007;67:8477-8485.  [PubMed]  [DOI]
77.  Togi S, Kamitani S, Kawakami S, Ikeda O, Muromoto R, Nanbo A, Matsuda T. HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A. Biochem Biophys Res Commun. 2009;379:616-620.  [PubMed]  [DOI]
78.  Lehmann A, Denkert C, Budczies J, Buckendahl AC, Darb-Esfahani S, Noske A, Müller BM, Bahra M, Neuhaus P, Dietel M. High class I HDAC activity and expression are associated with RelA/p65 activation in pancreatic cancer in vitro and in vivo. BMC Cancer. 2009;9:395.  [PubMed]  [DOI]
79.  Glauben R, Sonnenberg E, Zeitz M, Siegmund B. HDAC inhibitors in models of inflammation-related tumorigenesis. Cancer Lett. 2009;280:154-159.  [PubMed]  [DOI]
80.  Rosato RR, Kolla SS, Hock SK, Almenara JA, Patel A, Amin S, Atadja P, Fisher PB, Dent P, Grant S. Histone deacetylase inhibitors activate NF-kappaB in human leukemia cells through an ATM/NEMO-related pathway. J Biol Chem. 2010;285:10064-10077.  [PubMed]  [DOI]
81.  Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J. 2000;19:1176-1179.  [PubMed]  [DOI]
82.  Norris KL, Lee JY, Yao TP. Acetylation goes global: the emergence of acetylation biology. Sci Signal. 2009;2:pe76.  [PubMed]  [DOI]
83.  Smith KT, Workman JL. Introducing the acetylome. Nat Biotechnol. 2009;27:917-919.  [PubMed]  [DOI]
84.  Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834-840.  [PubMed]  [DOI]
85.  Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell. 2006;23:607-618.  [PubMed]  [DOI]
86.  Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6:38-51.  [PubMed]  [DOI]
87.  Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci USA. 2002;99:13653-13658.  [PubMed]  [DOI]
88.  Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol. 2002;158:647-657.  [PubMed]  [DOI]
89.  Januchowski R, Dabrowski M, Ofori H, Jagodzinski PP. Trichostatin A down-regulate DNA methyltransferase 1 in Jurkat T cells. Cancer Lett. 2007;246:313-317.  [PubMed]  [DOI]
90.  Xiong Y, Dowdy SC, Podratz KC, Jin F, Attewell JR, Eberhardt NL, Jiang SW. Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells. Cancer Res. 2005;65:2684-2689.  [PubMed]  [DOI]
91.  Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 2006;66:1277-1281.  [PubMed]  [DOI]
92.  Sadoul K, Boyault C, Pabion M, Khochbin S. Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie. 2008;90:306-312.  [PubMed]  [DOI]
93.  Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell. 2002;111:709-720.  [PubMed]  [DOI]
94.  Leduc C, Claverie P, Eymin B, Col E, Khochbin S, Brambilla E, Gazzeri S. p14ARF promotes RB accumulation through inhibition of its Tip60-dependent acetylation. Oncogene. 2006;25:4147-4154.  [PubMed]  [DOI]
95.  Ito A, Kawaguchi Y, Lai CH, Kovacs JJ, Higashimoto Y, Appella E, Yao TP. MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J. 2002;21:6236-6245.  [PubMed]  [DOI]
96.  Krämer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J. 2003;22:3411-3420.  [PubMed]  [DOI]
97.  Krämer OH, Müller S, Buchwald M, Reichardt S, Heinzel T. Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha. FASEB J. 2008;22:1369-1379.  [PubMed]  [DOI]
98.  Dasmahapatra G, Lembersky D, Kramer L, Fisher R, Friedberg J, Dent P, Grant S. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood. 2010;Epub ahead of print.  [PubMed]  [DOI]
99.  Heider U, Rademacher J, Lamottke B, Mieth M, Moebs M, von Metzler I, Assaf C, Sezer O. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma. Eur J Haematol. 2009;82:440-449.  [PubMed]  [DOI]
100.  Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S, Roden RB. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res. 2009;15:570-577.  [PubMed]  [DOI]
101.  Emanuele S, Lauricella M, Carlisi D, Vassallo B, D'Anneo A, Di Fazio P, Vento R, Tesoriere G. SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis. 2007;12:1327-1338.  [PubMed]  [DOI]
102.  Aoyagi S, Archer TK. Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol. 2005;15:565-567.  [PubMed]  [DOI]
103.  Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P. 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. 2005;280:26729-26734.  [PubMed]  [DOI]
104.  Scroggins BT, Robzyk K, Wang D, Marcu MG, Tsutsumi S, Beebe K, Cotter RJ, Felts S, Toft D, Karnitz L. An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell. 2007;25:151-159.  [PubMed]  [DOI]
105.  George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, Sigua C, Sondarva G, Moscinski L, Atadja P. 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. 2005;105:1768-1776.  [PubMed]  [DOI]
106.  Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7:1013-1030.  [PubMed]  [DOI]
107.  Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer. 2004;4:966-977.  [PubMed]  [DOI]
108.  Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403:98-103.  [PubMed]  [DOI]
109.  Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome c-independent activation of caspase-9 by caspase-12. J Biol Chem. 2002;277:34287-34294.  [PubMed]  [DOI]
110.  Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol. 2004;165:347-356.  [PubMed]  [DOI]
111.  Qu L, Huang S, Baltzis D, Rivas-Estilla AM, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A, Koromilas AE. Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev. 2004;18:261-277.  [PubMed]  [DOI]
112.  Kahali S, Sarcar B, Fang B, Williams ES, Koomen JM, Tofilon PJ, Chinnaiyan P. Activation of the unfolded protein response contributes toward the antitumor activity of vorinostat. Neoplasia. 2010;12:80-86.  [PubMed]  [DOI]
113.  Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42.  [PubMed]  [DOI]
114.  Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe K, Kamitsuji Y, Toyokuni SY. Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int J Cancer. 2009;124:55-67.  [PubMed]  [DOI]
115.  Yamamoto S, Tanaka K, Sakimura R, Okada T, Nakamura T, Li Y, Takasaki M, Nakabeppu Y, Iwamoto Y. Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res. 2008;28:1585-1591.  [PubMed]  [DOI]
116.  Oh M, Choi IK, Kwon HJ. Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun. 2008;369:1179-1183.  [PubMed]  [DOI]
117.  Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2004;101:18030-18035.  [PubMed]  [DOI]
118.  Carew JS, Medina EC, Esquivel JA 2nd, Mahalingam D, Swords R, Kelly K, Zhang H, Huang P, Mita AC, Mita MM. Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation. J Cell Mol Med. 2009;Epub ahead of print.  [PubMed]  [DOI]