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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate high-throughput screen, we identified a series of isothiazolone-based HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP-responsive element binding protein-binding protein-associated factor (PCAF) and p300 (1 to >50 micromol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 micromol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2-48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of alpha-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition.
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PMID:Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. 1622 1

Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.
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PMID:Crystal structure of a bacterial class 2 histone deacetylase homologue. 1624 51

Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, we have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homology model of HDAC8 with the recently published X-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homology models to understand the similarities and differences between the binding modes. Molecular dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.
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PMID:Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. 1625 Jun 52

Histone acetyltransferases and histone deacetylases are protein-modifying enzymes involved in addition and removal of acetyl groups on histone proteins, respectively. These molecules play a pivotal role in cellular functions such as chromosome remodelling, gene transcription and cell proliferation. Histone deacetylase inhibitors (HDIs) have been shown to cause cell cycle arrest, cellular differentiation and inhibition of cell proliferation in tumor cells in vitro and in vivo. Their potential use for cancer therapy is currently under evaluation in clinical trials. A pilot study was performed to immunohistochemically evaluate the effects of a HDI, "Compound 1", on acetylation, proliferation, mitosis, and apoptosis in tumor xenografts (Calu-6, SW 620, Colo 205, and LoVo) in nude mice, at 6, 24, and 48 hours, following a single oral dose. Qualitative immunohistochemistry and computer-assisted image analysis demonstrated an increase in acetylation in all xenografts. Immunohistochemical analysis of acetylation in skin showed increased acetylation at 6 hours after HDI administration. In addition, image analysis showed a decrease in mitosis and an increase in metaphase mitotic figures in the SW 620 xenograft. These two findings were consistent with a G1/S cell cycle phase arrest. Increased apoptosis of SW 620 and LoVo xenografts was also observed following treatment.
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PMID:Immunohistochemical analysis of acetylation, proliferation, mitosis, and apoptosis in tumor xenografts following administration of a histone deacetylase inhibitor--a pilot study. 1639 74

Histone-deacetylase inhibitors (HDCACi) represent a new class of antitumor agents currently in clinical development. They target a family of enzymes which catalyse histone acetylation modifications, in particular for histones H2A, H2B, H3 and H4. These proteins stabilize the nucleosome core, fundamental unity of chromatin which represents the first level of DNA nuclear compaction. The balance of histone acetylation is maintained by histone-acetyltransferases (HAT) and histone-deacetylases (HDAC) which play an important role in gene transcription. Alterations of HDACs were identified in tumor cells and contribute to the massive perturbations of gene expression in numerous tumors. HDAC inhibition leads to differentiation, cell cycle arrest and apoptosis in tumor cells. HDACi efficiently prevent tumor growth in a variety of in vivo preclinical models. Several structurally distinct classes of HDACi have entered in clinical trials and a significant antitumor activity was reported in several cases. However, a better understanding of the biological effects of this class of enzymes is mandatory for the successful development of these new antitumoral agents. In this review, are exposed the main drug candidates in clinical development. In the near future, it will be interesting to define direct relationships between specific inhibition of one or several HDAC and the subsequent HDAC-dependent antitumor effects to define a new generation of specific histone-deacetylase inhibitors.
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PMID:[Histone-deacetylases inhibitors: from TSA to SAHA]. 1645 3

Adrenocortical tumors in the pediatric population are rare. Classification of these tumors as adenomas or carcinomas using histological criteria is often difficult. Immunohistochemical expressions of proliferative markers are currently under investigation for utilization in the differential diagnosis and prediction of clinical outcomes. The value of histone proteins as prognostic markers in adrenocortical tumors has not yet been elucidated. We evaluated the histological features, immunohistochemical staining of Ki 67, and in situ hybridization for histone mRNA in 30 pediatric adrenocortical tumors. We investigated the relationship between these parameters and the prognosis. Using the classification proposed by Weiss, 19 tumors were classified as carcinomas and 11 as adenomas. Ki 67 and histone mRNA labeling indices (LIs, the percentage of Ki 67-positive and histone mRNA-positive tumor cells, respectively) were significantly higher in carcinomas than in adenomas (Ki 67 LI was 14.62+/-5.79 in adenomas and 20.35+/-6.23 in carcinomas, p=0.02. Histone mRNA LI was 1.73+/-1.71 in adenomas and 6.62+/-2.28 in carcinomas, p=0.00). The proliferative activity assessed by histone mRNA was lower than that assessed by Ki 67 in both diagnostic groups. The cut off point for the diagnosis of malignancy was found to be 14.55 for Ki 67 LI and 5.75 for histone mRNA LI. A correlation was found between a histone mRNA LI>or=5 and poor prognosis (recurrence, metastasis, or death). We concluded that the proliferative activity of the tumor assessed by Ki 67 and histone mRNA may assist in differentiating adrenocortical adenomas and carcinomas. In addition, our results suggest that the most reliable parameter to predict prognosis in pediatric adrenocortical tumors is the histone mRNA LI.
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PMID:Histone mRNA in situ hybridization and Ki 67 immunohistochemistry in pediatric adrenocortical tumors. 1648 41

The epigenetic marks on the IGF2R gene that encodes a receptor responsible for IGF-II degradation consist of differentially methylated DNA in association with multiple modifications on the associated histones. We review these epigenetic marks across various species during the evolution of IGF2R imprinting. Both IGF2 and IGF2R genesare imprinted in the mammal lineage that diverged from Monotremata approximately 150 million years ago. While IGF2 is consistently imprinted in all mammals following its divergence, IGF2R imprinting disappears in the Euarchonta lineage, including human species, approximately 75 million years ago. Differential DNA methylation marks on the two parental alleles correlate with imprinting in all imprinted genes including IGF2R. While the DNA methylation marks in the IGF2R promoter region 1 (DMR1) correlate with IGF2R allelic expression, the DNA methylation marks in the intron region 2 (DMR2) fail to correlate with IGF2R imprinting status in a number of species. Human IGF2R and mouse neuronal Igf2r are not imprinted despite the presence of DMR2. We have noted that human IGF2R is not imprinted in more than 100 informative samples including various tumor tissues. Furthermore, opossum (Marsupialia) IGF2R is consistently imprinted despite the absence of DMR2. These lines of evidence indicate that DNA methylation marks in DMR2 are neither necessary nor sufficient for consistent imprinting of IGF2R across species. Histone modification marks, however, correlate more consistently with the tissue-specific and species-specific imprinting status of IGF2R in human and mouse. Acetylated histone H3 and H4 and methylated lysine 4 of H3 (H3-K4Me) associate with transcriptionally active alleles while tri-methylated lysine 9 of H3 (H3-K9Me3) marks the silenced alleles. In the mouse, an antisense non-coding transcript called Air is transcribed from DMR2 on the paternal allele, and this imprinted transcript plays a central role in Igf2r imprinting. Mouse Igf2r imprinting depends on an Air RNA while the existence of AIR in other species is unknown. Overall, DNA methylation, histone acetylation, and histone methylation play a vital role in coordinating IGF2R allelic expression across all species. Rare monoallelic or skewed allelic expression of human IGF2R and their biological importance warrants further rigorous study.
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PMID:Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. 1657 81

Histone H2AX phosphorylated on Ser-139, defined as gammaH2AX, is a reporter of DNA double-strand breaks (DSBs). While H2AX undergoes phosphorylation after induction of DNA damage by genotoxic agents or during physiological events that involve DNA recombination, it also is phosphorylated in untreated normal and tumor cells. We recently reported that this constitutive H2AX phosphorylation (CHP) is markedly reduced by the antioxidant N-acetyl-L-cysteine (NAC), and postulated that it reflects the oxidative DNA damage ("endogenous DSBs") induced by reactive oxygen species (ROS) generated by metabolic activity during progression through the cell cycle. In the present study, we provide evidence that growth of cells from three human lymphoblastoid cell lines TK6, NH32 and WTK1 in the presence of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) led to a distinct reduction in the level of CHP. The reduction of CHP was more pronounced in S and G(2)M than in G(1) phase cells. Constitutive activation of ATM was also reduced. The data suggest that a decrease in a cell's metabolic activity as a result of inhibition of glycolysis by 2-DG reduces generation of ROS which leads to the reduction of oxidative DNA damage. The data also point out that ATM may play a role in CHP induced by oxidative DNA damage. Therefore, the assay of CHP by multiparameter cytometry provides the means to measure effects of antioxidants and metabolic inhibitors on endogenous oxidative DNA damage in relation to cell cycle phase.
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PMID:2-deoxy-D-glucose reduces the level of constitutive activation of ATM and phosphorylation of histone H2AX. 1662 6

Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes. One such histone modification, particularly at H3 and H4, is methylation at specific lysine (K) residues. Whereas histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 have been reported. Here, we generated a stable cell line overexpressing a dominant-negative point mutant, H3-K27R, to examine the role of that specific lysine in ovarian cancer. Expression of this construct resulted in loss of methylation at H3-K27, global reduction of DNA methylation, and increased expression of tumor suppressor genes. One of the affected genes, RASSF1, was shown to be a direct target of H3-K27 methylation-mediated silencing. By increasing DNA-platinum adduct formation, indicating increased access of the drug to target DNA sequences, removal of H3-K27 methylation resensitized drug-resistant ovarian cancer cells to the chemotherapeutic agent cisplatin. This increased platinum-DNA access was likely due to relaxation of condensed chromatin. Our results show that overexpression of mutant H3-K27 in mammalian cells represents a novel tool for studying epigenetic mechanisms and the Histone Code Hypothesis in human cancer. Such findings show the significance of H3-K27 methylation as a promising target for epigenetic-based cancer therapies.
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PMID:Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells. 1674 Jun 93

The structure and function of chromatin can be altered by modifications to histone. Histone acetylation is a reversible process governed by histone acetyltransferases and histone deacetylases (HDACs). HDAC6 is a subtype of the HDAC family that deacetylates alpha-tubulin and increases cell motility. We investigated the expression levels of HDAC6 mRNA and protein expression in oral squamous cell carcinoma (OSCC)-derived cell lines and human primary OSCCs to elucidate the potential involvement of HDAC6 in OSCC. Using quantitative real-time reverse transcription polymerase chain reaction and Western blots on nine OSCC-derived cell lines and normal oral keratinocytes (NOKs), HDAC6 mRNA and protein expression were commonly up-regulated in all cell lines compared with the NOKs. Immunofluorescence analysis detected HDAC6 protein in the cytoplasm of OSCC cell lines. Similar to OSCC cell lines, high frequencies of HDAC6 up-regulation were evident in both mRNA (74%) and protein (51%) levels of primary tumors. Among the clinical variables analyzed, the clinical tumor stage was found to be associated with the HDAC6 expression states. The analysis indicated a significant difference in the HDAC6 expression level between the early stage (stage I and II) and advanced-stage (stage III and IV) tumors (P=0.014). These results suggest that HDAC6 expression may be correlated with tumor aggressiveness and offer clues to the planning of new treatments.
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PMID:Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. 1677 91


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