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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear matrins are proteins that localize to the internal nuclear matrix. In a previous study, we reported that histone deacetylase is a component of the internal matrix, suggesting that histone deacetylase is a nuclear matrin. Here, we demonstrate that the majority of the histone deacetylase activity is associated with the internal nuclear matrices of chicken and trout liver. Thus, the association of the histone deacetylase with the internal nuclear matrix is neither tissue- nor species-specific. Using histone deacetylase as a marker enzyme for the partitioning of the internal nuclear matrix during nuclear fractionations, we show that in contrast to the internal nuclear matrices of trout liver, trout hepatocellular carcinoma and chicken liver, the stability of the chicken erythrocyte internal nuclear matrix is temperature-dependent. Our results support a model that has the histone deacetylase mediating transient interactions between the internal nuclear matrix and chromatin regions undergoing dynamic acetylation, for example transcriptionally active chromatin regions.
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PMID:Nuclear distribution of histone deacetylase: a marker enzyme for the internal nuclear matrix. 156 6

Treatment of Ehrlich ascites tumor cells with the alkylating antitumor agents triaziquonum, N-mustard and cyclophosphamide leads to a reduction in the posttranslational incorporation of 3H-acetate into histones and the extent of histone acetylation in Ehrlich ascites tumor cells. All core histones are affected. The depression of histone acetylation is not the result of a decrease in acetyl-CoA. Evidence is presented for an activation of histone deacetylase by alkylating agents. A reduction of histone deacetylation is observed after exposure to all concentrations of alkylating agents which inhibit cell proliferation. In order to evaluate the biological consequences of a reduction of histone acetylation, the extent of acetylation was modulated by either chemical acetylation or treatment with butyrate. In all cases an increase in histone acetylation leads to an enhancement of the rate of transcription. In accord with previous reports from our laboratory (1), it is concluded that the reduction of histone acetylation affects RNA synthesis. It is emphasized, however, that besides a regulation of transcription, histone acetylation may be involved in other cell functions. Thus, the complete biological consequences of the reduction of histone acetylation remain to be elucidated. In view of the antitumor activity of the alkylating agents it seems noteworthy that hepatoma AS30D cells are characterized by a remarkably higher extent of histone H4-acetylation compared to normal, adult, fetal, or regenerating liver.
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PMID:Depression of histone acetylation by alkylating antitumor agents: significance for antitumor activity and possible biological consequences. 647 41

Rare benzo[a]pyrene-resistant clones were previously isolated from the mouse hepatoma cell line, Hepa-1 (Hepa1c1c7), and shown to be deficient in induction of CYP1A1 mRNA by ligands for the aryl hydrocarbon receptor (AHR). Clones belonging to complementation group B were shown to have reduced levels of ligand binding to AHR. It is shown here that all 15 independently derived B clones analyzed had much reduced levels of AHR mRNA, but in each case, the mRNA was normal in size. Infection of B clones with a retroviral expression vector for AHR restores CYP1A1 inducibility (although viral AHR expression is progressively silenced and CYP1A1 expression progressively diminishes as the cells are maintained in culture). Treatment of the B clones with the histone deacetylase inhibitors sodium butyrate or trichostatin A restores AHR expression and also restores CYP1A1 inducibility to nearly 100% of the cells in the treated cultures. Fusion of a representative B clone with a rat hepatoma cell line restores expression to the mouse AHR gene encoded by the B clone's genome. These results demonstrate that the loss of CYP1A1 inducibility in B clones is probably totally ascribable to their reduced levels of AHR and that the clones are most probably not mutated in the AHR gene but are deficient in its expression. The evidence suggests that the reduction in expression of mRNA encoded by the endogenous AHR gene in the B clones is not due to an epigenetic alteration in chromatin structure but that the clones are probably defective either in a transcription factor for the AHR gene or in a protein required for generating an open chromatin configuration over the gene.
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PMID:Basis for the loss of aryl hydrocarbon receptor gene expression in clones of a mouse hepatoma cell line. 896 65

The interplay between the acetylation and deacetylation activities within the cell has been postulated to be a mechanism by which the cell regulates expression from genes at the level of chromatin. We have examined the expression pattern of the human histone deacetylase gene HDAC1 and the cyclin dependent kinase inhibitor p57Kip2 in the hepatocellular carcinoma cell line Hep 3B. HDAC1 expression was elevated at low cell densities, but once a critical threshold point in cell density was attained, expression was reduced to very low levels. Treatment of the cells with trichostatin A (TSA), a potent inhibitor of histone deacetylases, was found to affect expression. p57Kip2 was found to be downregulated by TSA, whereas HDAC1 was upregulated. These effects were found to be cell density dependent. The results suggest that HDAC1 plays a role in its own regulation, and that investigations using TSA should be carried out when cells grow exponentially.
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PMID:Effects of cell density and trichostatin A on the expression of HDAC1 and p57Kip2 in Hep 3B cells. 957 Nov 67

The tumor suppressor Bin1 was identified through its interaction with the N-terminal region of Myc which harbors its transcriptional activation domain. Here we show that Bin1 and Myc physically and functionally associate in cells and that Bin1 inhibits cell proliferation through both Myc-dependent and Myc-independent mechanisms. Bin1 specifically inhibited transactivation by Myc as assayed from artificial promoters or from the Myc target genes ornithine decarboxylase (ODC) and alpha prothymosin (pT). Inhibition of ODC but not pT required the presence of the Myc binding domain (MBD) of Bin1 suggesting two mechanisms of action. Consistent with this possibility, a non-MBD region of Bin1 was sufficient to recruit a repression function to DNA that was unrelated to histone deacetylase. Regions outside the MBD required for growth inhibition were mapped in Ras cotransformation or HepG2 hepatoma cell growth assays. Bin1 required the N-terminal BAR domain to suppress focus formation by Myc whereas the C-terminal U1 and SH3 domains were required to inhibit adenovirus E1A or mutant p53, respectively. All three domains contributed to Bin1 suppression of tumor cell growth but BAR-C was most crucial. These findings supported functional interaction between Myc and Bin1 in cells and indicated that Bin1 could inhibit malignant cell growth through multiple mechanisms.
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PMID:Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms. 1038 Aug 78

In previous studies, diallyl disulfide induced differentiation in DS19 mouse erythroleukemic cells. A mechanism mediated by increased histone acetylation was investigated. Diallyl disulfide caused increased acetylation of H4 and H3 histones in DS19 cells and K562 human leukemic cells. Diallyl disulfide was more effective than diallyl monosulfide and diallyl sulfone. Acetylation was also induced in rat hepatoma and human breast cancer cells by diallyl disulfide or its metabolite, allyl mercaptan. Allyl mercaptan was a more potent inhibitor of histone deacetylase than diallyl disulfide. Differentiation in erythroleukemic cells by diallyl disulfide and allyl mercaptan may be mediated through induction of histone acetylation.
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PMID:Increased acetylation of histones induced by diallyl disulfide and structurally related molecules. 1040 46

The mechanisms by which cells regulate gene expression are often altered in tumors. Modulating aspects of the components responsible for the nuclear packaging of DNA is one means by which the cell can control transcription, either by packaging the DNA such that access to specific sites of transcription is blocked or by modifying the DNA itself to prevent transcription factor binding. One such DNA modification is the methylation of cytosines. In addition, histone acetylation status has been linked recently through a large number of studies to the regulation of gene expression. Expressed genes are located in highly acetylated chromatin. The acetylation status of nucleosomes (the basic packaging unit of chromatin), is regulated by a group of enzymes, histone acetyltransferases (HATs), and histone deacetylases (HDACs). These two elements, methylation and histone acetylation have also been linked together, whereby methylation is used to direct gene repression through a histone deacetylase complex. Methylation, HATs, and HDACs have been shown to be altered in tumors. We present an overview of the current knowledge surrounding these elements in cancer, and in the final sections describe the likelihood of alterations of the histone modifying apparatus in hepatocellular carcinoma.
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PMID:Methylation, gene expression and the chromatin connection in cancer (review) 1049 73

The Hep3B cell line analyzed in the present study is a widely used in vitro model in studies characterizing pathogenetic, functional, and therapeutic aspects of human hepatocellular carcinoma (HCC). Here we have determined the chromosomal composition using a combination of cytogenetic techniques. In agreement with the original description for this cell line, Hep3B was found to have a hypotriploid chromosome content carrying 59-63 chromosomes and no cytogenetic differences were demonstrated between early and late passages suggesting that this cell line has remained stable after repeated subculturing. Mutations and alterations of the IGF-axis as well as of chromosome 1p34, where the genes for histone deacetylase 1 (HDAC1) and transforming growth factor beta receptor interacting protein-1 (TRIP-1) map, are frequent events in hepatocarcinogenesis. This study characterizes the Hep3B cell line in detail at the karyotypic level, using comparative genomic hybridization (CGH), spectral karyotyping (SKY), G-banding and FISH techniques. We have also examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on members of the IGF-axis, and analysed them with regard to the karyotype. The results show that expression of one member of the IGF-axis, IGFBP-3, is greatly upregulated by treatment of Hep3B cells with TSA. As IGFBP-3 has been shown to induce apoptosis, these results suggest a possible use for histone deacetylase inhibitors and/or IGFBP-3 in the treatment of HCC.
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PMID:Modulating IGFBP-3 expression by trichostatin A: potential therapeutic role in the treatment of hepatocellular carcinoma. 1060 71

Methionine adenosyltransferase (MAT) is the enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the main donor of methyl groups in the cell. In mammals MAT is the product of two genes, MAT1A and MAT2A. MAT1A is expressed only in the mature liver whereas fetal hepatocytes, extrahepatic tissues and liver cancer cells express MAT2A. The mechanisms behind the tissue and differentiation state specific MAT1A expression are not known. In the present work we examined MAT1A promoter methylation status by means of methylation sensitive restriction enzyme analysis. Our data indicate that MAT1A promoter is hypomethylated in liver and hypermethylated in kidney and fetal rat hepatocytes, indicating that this modification is tissue specific and developmentally regulated. Immunoprecipitation of mononucleosomes from liver and kidney tissues with antibodies mainly specific to acetylated histone H4 and subsequent Southern blot analysis with a MAT1A promoter probe demonstrated that MAT1A expression is linked to elevated levels of chromatin acetylation. Early changes in MAT1A methylation are already observed in the precancerous cirrhotic livers from rats, which show reduced MAT1A expression. Human hepatoma cell lines in which MAT1A is not expressed were also hypermethylated at this locus. Finally we demonstrate that MAT1A expression is reactivated in the human hepatoma cell line HepG2 treated with 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor trichostatin, suggesting a role for DNA hypermethylation and histone deacetylation in MAT1A silencing.
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PMID:Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation. 1062 84

Expression of the Bcl-2 family members in a human hepatocellular carcinoma cell line (HCC-T) after sodium butyrate-treatment was investigated. Sodium butyrate, a histone deacetylase inhibitor, induced differentiation of the cell line into its normal counterpart without inducing apoptosis at the concentration of 2 mmol/l. Since sodium butyrate has effects on both differentiation and apoptosis, we investigated the expression profile of bcl-2 related genes in HCC-T. The expression of Bcl-2 and Mcl-1/EAT was up-regulated 4-12 h after the treatment while Bcl-XL was up-regulated 2-3 days after the stimulation. On the other hand, the expression levels of Bax protein remained unchanged during differentiation. The HCC-T cells entered a cell cycle arrest at G1 and showed neither cellular fragmentation nor apoptosis during this period, which was concomitantly associated with up-regulated expression of a cell cycle regulator, p21WAF-1. These results demonstrate that induction of anti-apoptotic bcl-2 related proteins at an early stage of differentiation is important for the maintenance of HCC-T cell differentiation by antagonizing pro-apoptotic molecules such as Bax.
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PMID:Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period. 1067 72


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