Toward Selective Histone Deacetylase Inhibitor Design:  Homology Modeling, Docking Studies, and Molecular Dynamics Simulations of Human Class I Histone Deacetylases

Wang, Di-Fei; Helquist, Paul; Wiech, N. L.; Wiest, Olaf

doi:10.1021/jm0505011

Cited by 203 publications

(205 citation statements)

References 38 publications

Supporting

Mentioning

195

Contrasting

Order By: Relevance

“…Development of inhibitors with selective isoenzyme specificities seems to be feasible on the level of enzyme inhibition (15,(47)(48)(49) and HDAC protein degradation (50). The genetically defined model expressing a mutant protein that is inactive and does not integrate into multiprotein complexes (e.g., corepressor) corresponds closely to drug-induced degradation of HDAC2 but not fully to inhibition of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

Reduced Body Size and Decreased Intestinal Tumor Rates in HDAC2-Mutant Mice

Zimmermann¹,

Kiefer²,

Prudenziati

et al. 2007

Cancer Research

122

View full text Add to dashboard Cite

Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH 2 -terminal part of HDAC2 and B-galactosidase, which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are f25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I-induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I-dependent responses. Crossing of HDAC2-mutant with tumor-prone APC min mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Reduced Body Size and Decreased Intestinal Tumor Rates in HDAC2-Mutant Mice

Zimmermann¹,

Kiefer²,

Prudenziati

et al. 2007

Cancer Research

122

View full text Add to dashboard Cite

show abstract

“…2A). These correspond to Cys 261 and Cys 273 residues of HDAC1, which appear to be surface-accessible, according to homology models (35). Notably, HDAC8, which was not susceptible to alkylation by 15d-PGJ 2 -B, has a Leu substituted for Cys at one conserved position and a displaced Cys with a different flanking residue at the other conserved position.…”

Section: Alkylation (Carbonylation) Of Conserved Cysteine Residues Inmentioning

confidence: 91%

Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function

Doyle

Fitzpatrick

2010

Journal of Biological Chemistry

132

109

View full text Add to dashboard Cite

Cells use redox signaling to adapt to oxidative stress. For instance, certain transcription factors exist in a latent state that may be disrupted by oxidative modifications that activate their transcription potential. We hypothesized that DNA-binding sites (response elements) for redox-sensitive transcription factors may also exist in a latent state, maintained by co-repressor complexes containing class I histone deacetylase (HDAC) enzymes, and that HDAC inactivation by oxidative stress may antagonize deacetylase activity and unmask electrophile-response elements, thus activating transcription. Electrophiles suitable to test this hypothesis include reactive carbonyl species, often derived from peroxidation of arachidonic acid. We report that ␣,␤-unsaturated carbonyl compounds, e.g. the cyclopentenone prostaglandin, 15-deoxy-⌬12,14-PGJ 2 (15d-PGJ 2 ), and 4-hydroxy-2-nonenal (4HNE), alkylate (carbonylate), a subset of class I HDACs including HDAC1, -2, and -3, but not HDAC8. Covalent modification at two conserved cysteine residues, corresponding to Cys 261 and Cys 273 in HDAC1, coincided with attenuation of histone deacetylase activity, changes in histone H3 and H4 acetylation patterns, derepression of a LEF1⅐␤-catenin model system, and transcription of HDAC-repressed genes, e.g. heme oxygenase-1 (HO-1), Gadd45, and HSP70. Identification of particular class I HDACs as components of the redox/ electrophile-responsive proteome offers a basis for understanding how cells stratify their responses to varying degrees of pathophysiological oxidative stress associated with inflammation, cancer, and metabolic syndrome.Cellular oxidative stress can vary widely in severity and scope. Consequently, redox signaling must accommodate physiological demands from respiration, metabolism, host defense, cell replication, and aging plus demands from pathological oxidative stress encountered during inflammation, malignancy, reperfusion injury, and metabolic syndrome. Stimulus-response coupling in these different situations must be properly stratified; otherwise, maladaptation can have grave outcomes. An insufficient response to oxidative stress can lead to cell death, which typifies many neurodegenerative diseases. An excessive response to oxidative stress can lead to hypertrophy, hyperplasia, or neoplasia (1).Phenotypic adaptation to oxidative stress derives, in part, from the expression of genes to protect cells from damage, to repair damage, and to bolster their survival. This involves cellular proteins collectively termed the redox/electrophile-responsive proteome (2, 3). These proteins vary widely in cellular localization and functionality, but all have cysteine residues with distinctively nucleophilic thiols (pK a Յ 5), which are readily oxidized to sulfenic/sulfinic acids by reactive oxygen species (ROS) 2 or readily alkylated by reactive carbonyl species (RCS) (4, 5). RCS originate from either non-enzymatic or enzymatic peroxidation of lipids (especially arachidonic acid), which generates ␣,␤-unsaturated aldehydes (enals) (e.g....

show abstract

“…13,14 However, several factors, including the similarity between their catalytic sites, the difficulty in obtaining purified active proteins and until recently, lack of X-ray crystal structures, have hampered the search for potent isoform-specific inhibitors, and this in turn has slowed down the progress in delineating the biology of the individual HDAC isoforms in cancer. 15,16 Knockdown experiments of selective HDAC isoforms have revealed that HDAC8 is essential for cell survival. 17 HDAC8 is a 49 kDa HDAC isoform with deacetylase activity in vitro that is expressed in multiple tissue types and tumor cell lines.…”

Section: Introductionmentioning

confidence: 99%

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

et al. 2008

View full text Add to dashboard Cite

We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with 4200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-c1 (PLCc1)-defective line was resistant. Jurkat cells showed a dosedependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca 2 þ flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca 2 þ chelators (BAPTA) and enhanced by Ca 2 þ effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCc1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.

show abstract

Toward Selective Histone Deacetylase Inhibitor Design: Homology Modeling, Docking Studies, and Molecular Dynamics Simulations of Human Class I Histone Deacetylases

Cited by 203 publications

References 38 publications

Reduced Body Size and Decreased Intestinal Tumor Rates in HDAC2-Mutant Mice

Reduced Body Size and Decreased Intestinal Tumor Rates in HDAC2-Mutant Mice

Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

Contact Info

Product

Resources

About