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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase (HDAC) inhibitors are emerging as a promising new class of cancer therapeutic agents. HDAC inhibitors relieve the deacetylation of histone proteins. However, little is known about the nonhistone targets of HDAC inhibitors and their roles in gene regulation. In this study, we addressed the molecular basis of the down-regulation of the nuclear factor-kappaB (NF-kappaB)-responsive gene cyclin D1 by the HDAC inhibitor trichostatin A in mouse JB6 cells. Cyclin D1 plays a critical role in cell proliferation and tumor progression. Trichostatin A inhibits cyclin D1 expression in a NF-kappaB-dependent manner in JB6 cells. Electrophoretic mobility shift assay studies showed that trichostatin A treatment prevents p65 dimer binding to NF-kappaB sites on DNA. Moreover, a chromatin immunoprecipitation assay shows that trichostatin A treatment inhibits endogenous cyclin D1 gene transcription by preventing p65 binding to the cyclin D1 promoter. However, acetylation of p65 is not affected by trichostatin A treatment. Instead, trichostatin A enhances p52 acetylation and increases p52 protein level by enhancing p100 processing. This is the first report that trichostatin A, a HDAC inhibitor, activates p100 processing and relieves the repression of p52 acetylation. The enhanced acetylation of p52 in the nuclei may operate to cause nuclear retention of p65 by increasing the p52/p65 interaction and preventing IkappaBalpha-p65 binding. The enhanced p52 acetylation coincides with decreased p65 DNA binding, suggesting a potential role of p52 acetylation in NF-kappaB regulation. Together, the results provide the first demonstration that HDAC inhibitor trichostatin A inhibits cyclin D1 gene transcription through targeting transcription factor NF-kappaB/p65 DNA binding. NF-kappaB is therefore identified as a transcription factor target of trichostatin A treatment.
Mol Cancer Res 2005 Feb
PMID:Histone deacetylase inhibition down-regulates cyclin D1 transcription by inhibiting nuclear factor-kappaB/p65 DNA binding. 1575 76

Increasing survival motor neuron 2 (SMN2) gene expression may be an effective strategy for the treatment of spinal muscular atrophy (SMA). Histone deacetylase (HDAC) inhibitors have been shown to increase SMN transcript and protein levels, but the specific role of histone acetylation in regulating SMN gene expression has not been explored. Using chromatin immunopreciptation, we investigated the levels of acetylated H3 and H4 histones and HDACs associated with different regions of the human and mouse SMN genes in both cultured cells and tissues. We show that the SMN gene has a reproducible pattern of histone acetylation that is largely conserved among different tissues and species. A limited region of the promoter surrounding the transcriptional start site has relatively high levels of histone acetylation, whereas regions further upstream or downstream have lower levels. After HDAC inhibitor treatment, acetylated histone levels increased, particularly at upstream regions, correlating with a 2-fold increase in promoter activity. During development in mouse tissues, histone acetylation levels decreased and associated HDAC2 levels increased at the region closest to the transcriptional start site, correlating with a 40-60% decrease in SMN transcript and protein levels. These data indicate that histone acetylation modulates SMN gene expression and that pharmacological manipulation of this epigenetic determinant is feasible. HDAC2, in particular, may be a future therapeutic target for SMA.
Hum Mol Genet 2005 May 01
PMID:The role of histone acetylation in SMN gene expression. 1577 88

In breast cancer, radiation has a central role in the treatment of brain metastasis, although tumor sensitivity might be limited. The tumor cell defense response to ionizing radiation involves activation of cell cycle checkpoint signaling. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby aberrations in the chromatin structure, may also override the DNA damage defense response and facilitate the radiation-induced mitotic cell death. In experimental metastasis models, the human breast carcinoma cell line MA-11 invariably disseminates to the central nervous system. We compared profiles of in vitro MA-11 cell cycle response to ionizing radiation and HDAC inhibition. After radiation exposure, the G2-M phase accumulation and the preceding repression of the G2 phase regulatory factors Polo-like kinase-1 and cyclin B1 required intact G2 checkpoint signaling through the checkpoint kinase CHK1, whereas the similar phenotypic changes observed with HDAC inhibition did not. MA-11 cells did not show radiation-induced expression of the G1 cell cycle inhibitor p21, indicative of a defective G1 checkpoint and consistent with a point mutation detected in the tumor suppressor TP53 gene. Increase in the p21 level, however, was observed with HDAC inhibition. Following pretreatment with the HDAC inhibitor, the efficiency of clonogenic regrowth after irradiation was reduced, which is in accordance with the concept of increased probability of mitotic cell death when the chromatin structure is disrupted. Among molecular cell cycle-targeted drugs currently in the pipeline for testing in early-phase clinical trials, HDAC inhibitors may have therapeutic potential as radiosensitizers.
Mol Cancer Ther 2005 Aug
PMID:Cell cycle checkpoint signaling involved in histone deacetylase inhibition and radiation-induced cell death. 1609 39

Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two members of the steroid receptor family with cell growth regulatory properties. Like other transcription factors, steroid receptors modulate histone acetylation on target promoters. Using episomal reporter vectors containing minimal promoters to avoid promoter-specific effects, we observed that long-term (24-h) incubation with HDACi strongly stimulated GR-dependent but markedly repressed ER-dependent signaling in ER+/GR+ human endometrial carcinoma Ishikawa cells. These effects were reproduced on endogenous target genes and required incubation periods with HDACi substantially longer than necessary to increase global histone acetylation. Repression of estrogen signaling was due to direct inhibition of transcription from multiple ERalpha promoters and correlated with decreased histone acetylation of these promoters. In contrast, the strong HDACi stimulation of GR-dependent gene regulation was not accounted for by increased GR expression, but it was mimicked by overexpression of the histone acetyltransferase complex component transcriptional intermediary factor 2. Together, our results demonstrate striking and opposite effects of HDACi on ER and GR signaling that involve regulatory events independent of histone hyperacetylation on receptor target promoters.
Mol Pharmacol 2005 Dec
PMID:Opposite effects of histone deacetylase inhibitors on glucocorticoid and estrogen signaling in human endometrial Ishikawa cells. 1618 50

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.
J Mol Biol 2005 Nov 18
PMID:Crystal structure of a bacterial class 2 histone deacetylase homologue. 1624 51

Histone acetylation is involved in the regulation of gene expression in plants and eukaryotes. Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from histones, which is associated with the repression of gene expression. To study the role of histone acetylation in the regulation of gene expression during seed germination, trichostatin A (TSA), a specific inhibitor of histone deacetylase, was used to treat imbibing Arabidopsis thaliana seeds. GeneChip arrays were used to show that TSA induces up-regulation of 45 genes and down-regulation of 27 genes during seed germination. Eight TSA-up-regulated genes were selected for further analysis - RAB18, RD29B, ATEM1, HSP70 and four late embryogenesis abundant protein genes (LEA). A gene expression time course shows that these eight genes are expressed at high levels in the dry seed and repressed upon seed imbibition at an exponential rate. In the presence of TSA, the onset of repression of the eight genes is not affected but the final level of repressed expression is elevated. Chromatin immunoprecipitation and HDAC assays show that there is a transient histone deacetylation event during seed germination at 1 day after imbibition, which serves as a key developmental signal that affects the repression of the eight genes.
Plant Mol Biol 2005 Dec
PMID:Dynamic histone acetylation of late embryonic genes during seed germination. 1630 66

Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate (AN-1), induced hyperacetylation, increased p21(Cip1) expression, inhibited proliferation, and enhanced apoptosis. Histone deacetylase inhibitor-induced apoptosis was mediated primarily by caspase-8. Treatment of cells with AN-1 or AN-9 for 24 hours before exposure to gamma-irradiation potentiated further caspase-8 activity and resultant apoptosis. Clonogenic survival curves revealed marked reductions in cell renewal capacity of U251 MG cells exposed to combinations of AN-1 and radiation. Preliminary in vivo experiments using human glioma cell lines grown as xenografts in mouse flanks suggest in vivo efficacy of AN-9. The data suggest that novel butyric acid prodrugs provide a promising treatment strategy for malignant gliomas as single agents and in combination with radiation therapy.
Mol Cancer Ther 2005 Dec
PMID:Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas. 1637 10

Histone deacetylase inhibitors (HDACi) are a promising class of anticancer agents, yet the specific biological effects resulting in cell death are still poorly understood and clinically relevant markers of response are not adequately defined. The anticonvulsant valproic acid has recently emerged as an HDACi, and in vitro studies suggested that valproic acid may potentiate cytotoxic agents. We evaluated the pharmacologic and biological effects of valproic acid on histone acetylation, chromatin structure, and DNA damage induced by topoisomerase II inhibitors in mice bearing breast cancer tumors and developed an ex vivo methodology for response prediction using comet assays. The exposure of mice to valproic acid before exposure to epirubicin led to tumor regression when valproic acid was given for 48 hours at concentrations sufficient for histone hyperacetylation, down-regulation of heterochromatin maintenance proteins, and chromatin decondensation. Tumor response was accurately predicted by ex vivo comet moments. Valproic acid did not exacerbate epirubicin-related toxicity. Antitumor effects were not observed with valproic acid alone despite biologically active valproic acid concentrations. These findings suggest that exposure of tumor-bearing mice to valproic acid potentiated the antitumor effects of topoisomerase II inhibitors without enhancing toxicity. The HDACi-induced histone acetylation and modulation of heterochromatin correlated with potentiation of epirubicin-mediated DNA damage. However, these effects did not result in antitumor activity when using a HDACi alone and hence should not be considered a surrogate marker. Ex vivo comet assays may be useful as a predictive tool when tumor cells are limited and serial biopsies are difficult to obtain.
Mol Cancer Ther 2005 Dec
PMID:In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. 1637 14

Histone deacetylase inhibitors (HDACIs) can inhibit cell proliferation, induce cell cycle arrest, and stimulate the apoptosis of cancer cells. We investigated the effects of a novel HDACI, Scriptaid, on the Ishikawa endometrial cancer cell line, SK-OV-3 ovarian cancer cell line, and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of Scriptaid, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of Scriptaid, although normal endometrial epithelial cells were viable after treatment with the same doses of Scriptaid that induced the growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to Scriptaid decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 and/or G2/M phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with the altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, Scriptaid treatment of these cell lines increased acetylation of H3 and H4 histone tails. These results raise the possibility that Scriptaid may prove particularly effective in the treatment of endometrial and ovarian cancers.
Int J Mol Med 2006 Feb
PMID:A novel histone deacetylase inhibitor, Scriptaid, induces growth inhibition, cell cycle arrest and apoptosis in human endometrial cancer and ovarian cancer cells. 1639 33

Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1alpha expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1alpha expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1alpha levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1alpha by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1alpha with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.
Mol Cell Biol 2006 Mar
PMID:Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. 1650 82


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