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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 belong to a promising class of antineoplastic agents which affect tumor growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro on preclinical colon and pancreatic cancer models. Human colon adenocarcinoma HT-29 and pancreatic carcinoma DanG cells were treated with 1 mM VPA for different time periods during cell proliferation MTT assays, and to evaluate the tumor cell adhesion to endothelial cell monolayers. Alterations of beta1 integrin subunits alpha1-6) were analyzed by flow cytometry and RT-PCR. VPA significantly caused growth arrest in tumor cells and prevented tumor cell attachment to the endothelium. HT-29 cell adhesion was blocked to a higher extent than the adhesion of DanG cells. VPA modified membranous integrin beta1 expression, quantity and quality (up- or down-regulation) which depended on the tumor type investigated. Furthermore, VPA diminished integrin coding mRNA in HT-29 but not in DanG cells. We conclude that VPA shifts the integrin beta1 subunit balance from a 'pathological' towards a 'physiological' expression pattern leading to reduced tumor growth and invasion. Further study is required to elucidate the molecular background of the post-transcriptional modifications of VPA in order to exploit the potential of this agent in the treatment of colon and pancreatic cancer.
Int J Mol Med 2008 Sep
PMID:Modulation of adhesion and growth of colon and pancreatic cancer cells by the histone deacetylase inhibitor valproic acid. 1869 87

Histone deacetylase inhibitors (HDACis) are emerging as promising and selective antitumor agents. However, HDACis can lead to tumor stasis rather than shrinkage, in which case, traditional imaging methods are not adequate to monitor response. Consequently, novel approaches are needed. We have shown in cells that (19)F magnetic resonance spectroscopy (MRS)-detectable levels of the HDAC substrate Boc-Lys-TFA-OH (BLT) are inversely correlated with HDAC activity. We extended our investigations to a tumor xenograft model. Following intraperitoneal injection of BLT, its accumulation within the tumor was monitored by in vivo (19)F MRS. In animals treated with the HDACi suberoylanilide hydroxamic acid (SAHA), tumoral BLT levels were higher by 77% and 132% on days 2 and 7 of treatment compared with pretreatment levels (n = 6; p < .05). In contrast, tumoral BLT levels remained unchanged in control animals and in normal tissue. Thus, (19)F MRS of BLT detected the effect of HDACi treatment as early as day 2 of treatment. Importantly, tumor size confirmed that SAHA treatment leads to inhibition of tumor growth. However, difference in tumor size reached significance only on day 6 of treatment. Thus, this work identifies BLT as a potential molecular imaging agent for the early noninvasive MRS detection of HDAC inhibition in vivo.
Mol Imaging
PMID:Monitoring histone deacetylase inhibition in vivo: noninvasive magnetic resonance spectroscopy method. 1870 91

Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.
Environ Mol Mutagen 2009 Apr
PMID:Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. 1919 85

Histone deacetylase inhibitors are potent inducers of growth arrest and apoptotic cell death and are currently in clinical studies for solid tumors. In addition, recent studies from our own group provide evidence for an anti-inflammatory potency of HDACi in vitro and in vivo by using various models of experimental colitis. Since inflammatory bowel disease in humans is associated with an increased risk of developing colorectal cancer, a therapeutic approach combining anti-inflammatory as well as antiprolif-erative properties is highly intriguing. Consequently, methods to further characterize the mechanisms involved include the direct analysis of the acetylation/deacetylation as well as the regulatory effect of histone deacetylase inhibitors on defined cell populations.
Methods Mol Biol 2009
PMID:Molecular basis of histone deacetylase inhibitors as new drugs for the treatment of inflammatory diseases and cancer. 1934 89

Histone deacetylase inhibitors such as valproic acid (VPA) are promising anticancer agents that change the acetylation status of histones and loosen the chromatin structure. We assessed nuclear structure changes induced by VPA in prostate cancer LNCaP, CWR22R, DU145, and PC3 cell lines and xenografts and their potential use as a biomarker of treatment. In vitro tissue microarrays consisted of prostate cancer cell lines treated for 3, 7, or 14 days with 0, 0.6, or 1.2 mmol/L VPA. In vivo tissue microarrays consisted of cores from prostate cancer xenografts from nude mice treated for 30 days with 0.2% or 0.4% VPA in drinking water. Digital images of at least 200 Feulgen DNA-stained nuclei were captured using the Nikon CoolScope and nuclear alterations were measured. With a set of seven most frequently significant nuclear alterations (determined by univariate logistic regression analysis), control and VPA treatment nuclei were compared in vitro and in vivo. Depending on the cell line, area under the curve-receiver operating characteristics ranged between 0.6 and 0.9 and were dose- and time-dependent both in vitro and in vivo. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). In vitro and in vivo VPA treatment of prostate cancer cell lines results in significant dose- and time-dependent changes in nuclear structure. Further, VPA induces nuclear structural changes in normal liver and kidney tissue, which likely reflects a natural physiologic response. Therefore, nuclear structural alterations may serve as a biomarker for histone deacetylase inhibitor treatment.
Mol Cancer Ther 2009 Apr
PMID:Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo. 1937 53

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from the epsilon-amino groups of conserved lysine residues in the amino terminal tail of histones. In humans, there are 18 potential deacetylase enzymes that are responsible for the removal of acetyl groups and maintenance of the equilibrium of lysine acetylation on histones. Like most histone modification enzymes, accumulating evidence suggests that many, if not all, HDACs can also modify non-histone proteins. The focus of this article is to provide up-to-date, easy to follow, approaches and techniques specifically for the assay of HDAC enzymatic activities.
Methods Mol Biol 2009
PMID:Histone deacetylase activity assay. 1938 32

Histone deacetylase (HDAC) inhibitors represent a promising new avenue of therapeutic options for a range of neurological disorders. Within any particular neurological disorder, neuronal damage or death is not widespread; rather, particular brain regions are preferentially affected. Different disorders exhibit distinct focal pathologies. Hence, understanding the region-specific effects of HDAC inhibitors is essential for targeting appropriate brain areas and reducing toxicity in unaffected areas. The outcome of HDAC inhibition depends on several factors, including the diversity in the central nervous system expression of HDAC enzymes, selectivity of a given HDAC inhibitor for different HDAC enzymes, and the presence or absence of cofactors necessary for enzyme function. This review will summarize brain regions associated with various neurological disorders and factors affecting the consequences of HDAC inhibition.
Mol Neurobiol 2009 Aug
PMID:Focal nature of neurological disorders necessitates isotype-selective histone deacetylase (HDAC) inhibitors. 1939 37

Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with antiapoptotic properties. We present here the mechanism for repression of the Grp78 promoter by HDAC1. Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before, but not after, ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor-induced apoptosis in cancer cells, and conversely, suppression of GRP78 sensitizes them to HDAC inhibitors. These results define HDAC inhibitors as new agents that up-regulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anticancer therapies that use these compounds.
Mol Cancer Ther 2009 May
PMID:Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. 1941 44

Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anti-cancer agents for the treatment of solid and hematological malignancies. However, the best characterized HDAC function concerns the control of gene expression via the regulation of transcription activation or repression. To understand the genome-wide effects of HDAC inhibition on gene regulation, we performed serial gene expression analyses from 0 to 48 h after treating MDA-MB-435, a melanoma-derived highly metastatic tumor cell line, with Apicidin, a HDAC inhibitor. Combined-transcriptomic analysis of large-scale molecular changes induced by Apicidin resulted in the identification of 631 outlier genes that were continuously up- or down-regulated during the 48 h study period. When the 631 outlier genes were mapped to known biological processes, cell-cycle suppression emerged as the function most elicited by Apicidin. In addition comprehensive negative cell-cycle regulation by Apicidin was dissected using gene expression data and validated by Western blot analysis. We suggest the 631 outlier genes as a characteristic molecular signature for Apicidin, and propose concurrent transcriptional suppression of major components of cell-cycle regulatory circuit as potent anti-tumor mechanism of Apicidin. Genetic elements identified during this study also provide the possibility of novel therapeutic interventions in tumor metastasis.
Int J Mol Med 2009 Aug
PMID:Systemic cell-cycle suppression by Apicidin, a histone deacetylase inhibitor, in MDA-MB-435 cells. 1957 94

Histone deacetylase inhibitors (HDACi) are potential candidates for therapeutic approaches in cancer and neurodegenerative diseases such as spinal muscular atrophy (SMA)--a common autosomal recessive disorder and frequent cause of early childhood death. SMA is caused by homozygous absence of SMN1. Importantly, all SMA patients carry a nearly identical copy gene, SMN2, that produces only minor levels of correctly spliced full-length transcripts and SMN protein. Since an increased number of SMN2 copies strongly correlates with a milder SMA phenotype, activation or stabilization of SMN2 is considered as a therapeutic strategy. However, clinical trials demonstrated effectiveness of the HDACi valproate (VPA) and phenylbutyrate only in <50% of patients; therefore, identification of new drugs is of vital importance. Here we characterize the novel hydroxamic acid LBH589, an HDACi already widely used in cancer clinical trials. LBH589 treatment of human SMA fibroblasts induced up to 10-fold elevated SMN levels, the highest ever reported, accompanied by a markedly increased number of gems. FL-SMN2 levels were increased 2-3-fold by transcription activation via SMN2 promoter H3K9 hyperacetylation and restoration of correct splicing via elevated hTRA2-beta1 levels. Furthermore, LBH589 stabilizes SMN by reducing its ubiquitinylation as well as favouring incorporation into the SMN complex. Cytotoxic effects were not detectable at SMN2 activating concentrations. Notably, LBH589 also induces SMN2 expression in SMA fibroblasts inert to VPA, in human neural stem cells and in the spinal cord of SMN2-transgenic mice. Hence, LBH589, which is active already at nanomolar doses, is a highly promising candidate for SMA therapy.
Hum Mol Genet 2009 Oct 01
PMID:LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate. 1958 83


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