Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of various reports describing differences in histone acetylation between normal rat liver and hepatomas, the behaviour of histone acetyltransferase (EC 2.3.1.48) activity was elucidated in normal rat liver and in a spectrum of well-characterized rat hepatomas of slow, intermediate and rapid growth rates. In all tumours the acetyltransferase specific activity, expressed as nmol h-1 mg total protein-1, was higher than in the corresponding normal livers and the rise correlated positively with the proliferation rates of the tumors. No difference is observed if acetyltransferase activity is expressed per milligram of histone. This is explained by elevated ratios of histones and of DNA to total protein in the hepatomas compared to the ratios in normal liver. Electrophoretic analysis of [3H]acetate-labeled histones revealed similar patterns in hepatoma and normal liver. The extent of histone H4 acetylation, as indicated by the frequency distribution of non-, mono-, di-, tri-, and tetraacetylated H4-species, was found to be identical in hepatomas and normal liver. The histone protein and acetate labeling patterns were near normal in the slowly growing hepatomas.
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PMID:Histone acetyltransferase activity in rat hepatomas. 280 81

Pulse-chase experiments with [3H]lysine-labeled tissue culture cells reveal that newly synthesized nucleosomal histones H2B, H3, H4 (and possibly H2A) in chromatin are more accessible to histone acetylase in vivo than are older, pre-existing histones. Thus, when rat hepatoma cells are first pulse-labeled and then incubated in medium containing n-butyrate which blocks histone deacetylation, these newly synthesized histones become acetylated to a far greater extent than do their older homologues. As judged by its increased susceptibility to acetylation, the new chromatin matures at a surprisingly slow rate, the estimated half-time for maturation being about 35 min. Based on this data, we suggest that newly synthesized chromatin is in a relatively extended, accessible conformation, and that it slowly returns to a more compact conformation as it matures.
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PMID:Accessibility of newly synthesized chromatin to histone acetylase. 706 19

Aberrant expression of the alpha-fetoprotein (AFP) gene is characteristic of a majority of hepatocellular carcinoma cases and serves as a diagnostic tumor-specific marker. By dissecting regulatory mechanisms through electromobility gel shift, transient-transfection, Western blot, and in vitro transcription analyses, we find that AFP gene expression is controlled in part by mutually exclusive binding of two trans-acting factors, p53 and hepatic nuclear factor 3 (HNF-3). HNF-3 protein activates while p53 represses AFP transcription through sequence-specific binding within the previously identified AFP developmental repressor domain. A single mutation within the DNA binding domain of p53 protein or a mutation of the p53 DNA binding element within the AFP developmental repressor eliminates p53-repressive effects in both transient-transfection and cell-free expression systems. Coexpression of p300 histone acetyltransferase, which has been shown to acetylate p53 and increase specific DNA binding, amplifies the p53-mediated repression. Western blot analysis of proteins present in developmentally staged, liver nuclear extracts reveal a one-to-one correlation between activation of p53 protein and repression of AFP during hepatic development. Induction of p53 in response to actinomycin D or hypoxic stress decreases AFP expression. Studies in fibroblast cells lacking HNF-3 further support a model for p53-mediated repression that is both passive through displacement of a tissue-specific activating factor and active in the presence of tissue-specific corepressors. This mechanism for p53-mediated repression of AFP gene expression may be active during hepatic differentiation and lost in the process of tumorigenesis.
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PMID:p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding. 989 Oct 62

The carcinogenicity of specific insoluble nickel compounds is mainly due to their intracellular generation of Ni2+ ion and its suppression on gene transcription, while the inhibition of Ni2+ on histone acetylation plays an important role in the suppression or silencing of genes. Recent studies on Ni2+ and histone H4 acetylation suggest that Ni2+ inhibits the acetylation of histone H4 through binding with its N-terminal histidine-18. It is well known that bound Ni2+ readily produces reactive oxygen species (ROS) in vivo, a critical factor inversely related with the occurrence of resistance of mammalian cells to Ni2+. Thus, we tried to find the possible role of ROS in the induction of Ni2+ on histone acetylation in the present study. We found that a high concentration of Ni2+ (no less than 600 microM) caused a significant decrease of histone acetylation in human hepatoma cells. This inhibition was shown to result mainly from the influence of Ni2+ on the overall histone acetyltransferase (HAT) activity indicated by the histone acetylation assay with the presence of a specific histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). The in vitro HAT and HDAC assays further confirmed this result. At the same time, we found that the exposure of hepatoma cells to Ni2+ generated ROS. Coadministration of hydrogen peroxide with Ni2+ generated more ROS and more histone acetylation inhibition. Addition of the antioxidants 2-mercaptoethanol (2-ME) at 2 mM or N-acetyl-cysteine (NAC) at 1 mM, with Ni2+ together, completely suppressed ROS generation and significantly diminished the induced histone hypoacetylation. The data presented here prove that the ROS generation plays a role in the inhibition of histone acetylation, and, hence, the gene suppression and carcinogenesis caused by Ni2+ exposure, providing a new door for us to continuously understand the mechanism of ROS in the carcinogenicity of Ni2+ and the resistance of mammalian cells to Ni2+.
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PMID:Nickel-induced histone hypoacetylation: the role of reactive oxygen species. 1277 60

Cytochrome P-450 1A1 (CYP1A1) is known to be induced by aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), through activation of the aryl hydrocarbon receptor (AhR). We found that p38 MAP kinase inhibitors (SB203580 and SB202190; 40 microm each; pyridinyl imidazole compounds) suppressed CYP1A1-mRNA induction by TCDD (2 nm) in mouse hepatoma Hepa-1 cells and in human hepatoma HepG2 cells, and also suppressed CYP1B1-mRNA induction by TCDD (2 nm) in human breast adenocarcinoma MCF7 cells. An analogue compound, SB202474, which does not inhibit p38 MAP kinase, also suppressed CYP1A1-mRNA induction by TCDD. Moreover, overexpression of a dominant-negative gene for p38 MAP kinase in Hepa-1 cells did not suppress Cyp1a1 reporter gene induction by TCDD. Therefore, the suppression of Cyp1a1 transcription by pyridinyl imidazole compounds is not because of their inhibition of p38 MAP kinase activity. Because SB203580 did not inhibit in vitro AhR transformation by TCDD, this compound was not acting as a simple AhR antagonist. SB203580 decreased TCDD-induced histone acetylation levels in the region of the Cyp1a1 gene promoter, especially around the TATA box sequence. This result suggests the possibility that pyridinyl imidazole compounds suppress the recruitment of some co-activator that has the histone acetyltransferase activity necessary for CYP1A1-mRNA transcription.
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PMID:Suppression by p38 MAP kinase inhibitors (pyridinyl imidazole compounds) of Ah receptor target gene activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the possible mechanism. 1459 46

The abnormal accumulation of Cu2+ is closely correlated with the incidence of different diseases, such as Alzheimer's disease and Wilson disease. To study in vivo functions of Cu2+ will lead to a better understanding of the nature of these diseases. In the present study, effect of Cu2+ on histone acetylation was investigated in human hepatoma cells. Exposure of cells to Cu2+ resulted in a significant decrease of histone acetylation, as indicated by the decrease of the overall histone acetylation and the decrease of histone H3 and H4 acetylation. Since histone acetyltransferase (HAT) and histone deacetylase (HDAC) are the enzymes controlled the state of histone acetylation in vivo, we tested their contribution to the inhibition of Cu2+ on histone acetylation. One hundred nanomolar trichostatin A, the specific inhibitor of HDAC, did not attenuate the inhibitory effect of Cu2+ on histone acetylation. Combined with that Cu2+ showed no effect on the in vitro activity of HDAC, these results led to the conclusion that it is HAT, but not HDAC that is involved in Cu2+ -induced histone hypoacetylation. This conclusion was confirmed by the facts that (1) Cu2+ significantly inhibited the in vitro activity of HAT, (2) Cu2+ -treated cells possessed a lower HAT activity than control cells, and (3) 50 or 100 microM bathocuproine disulfonate, a chelator of Cu2+, significantly attenuated the inhibition of Cu2+ on HAT activity and histone acetylation in the similar pattern. Combined with that Cu2+ showed no or obvious cytotoxicity at 100 or 200 microM in human hepatoma cells, and the previous study that Cu2+ inhibits the histone H4 acetylation of yeast cells at nontoxic or toxic levels, the data presented here suggest that inhibiting histone acetylation is probably one general in vivo function of Cu2+, where HAT is its molecular target.
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PMID:Copper induces histone hypoacetylation through directly inhibiting histone acetyltransferase activity. 1527 68

The 1,10-orthophenanthroline (OP)-Cu(2+) combination, one generally used reactive oxygen species (ROS) generation system, is known to induce cell apoptosis, but the mechanism of ROS generation in this process remains unclear. Here we found that in the presence of 5 microM Cu(2+), OP inhibited histone acetyltransferase (HAT) activity, resulting in decreased acetylation in both histone H3 and H4. This inhibition of histone acetylation and HAT activity was significantly attenuated by preventing or scavenging ROS generation with the Cu(2+) chelator of bathocuproine disulfonate, or the antioxidants of N-acetyl-cysteine and mannitol, respectively, indicating the involvement of ROS generation in OP-Cu(2+) -induced histone hypoacetylation. At the same time, this ROS generation is found to be involved in OP-Cu(2+) -induced apoptosis in human hepatoma Hep3B cells. The important role of histone hypoacetylation in the induction of apoptosis was also proven by the marked diminution of apoptosis by 100 nM trichostatin A, a specific inhibitor of histone deacetylase, or the overexpression of p300, an HAT protein. Collectively, these observations suggest that histone hypoacetylation represents one unrevealed mechanism involved in the in vivo function of OP-Cu(2+) -generated ROS, at least in their induction of cell apoptosis.
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PMID:Histone hypoacetylation is involved in 1,10-phenanthroline-Cu2+-induced human hepatoma cell apoptosis. 1581 9

We previously demonstrated that formation of complexes between the DNA-binding domains of hepatocyte nuclear factor 6 (HNF6) and forkhead box a2 (Foxa2) proteins stimulated Foxa2 transcriptional activity. Here, we used HepG2 cell cotransfection assays to demonstrate that HNF6 transcriptional activity was stimulated by CCAAT/enhancer-binding protein alpha (C/EBPalpha), but not by the related C/EBPbeta or C/EBPdelta proteins. Formation of the C/EBPalpha-HNF6 protein complex required the HNF6 cut domain and the C/EBPalpha activation domain (AD) 1/AD2 sequences. This C/EBPalpha-HNF6 transcriptional synergy required both the N-terminal HNF6 polyhistidine and serine/threonine/proline box sequences, as well as the C/EBPalpha AD1/AD2 sequences, the latter of which are known to recruit the CREB binding protein (CBP) transcriptional coactivator. Consistent with these findings, adenovirus E1A-mediated inhibition of p300/CBP histone acetyltransferase activity abrogated C/EBPalpha-HNF6 transcriptional synergy in cotransfection assays. Co-immunoprecipitation assays with liver protein extracts demonstrate an association between the HNF6 and C/EBPalpha transcription factors and the CBP coactivator protein in vivo. Furthermore, chromatin immunoprecipitation assays with hepatoma cells demonstrated that increased levels of both C/EBPalpha and HNF6 proteins were required to stimulate association of these transcription factors and the CBP coactivator protein with the endogenous mouse Foxa2 promoter region. In conclusion, formation of the C/EBPalpha-HNF6 protein complex stimulates recruitment of the CBP coactivator protein for expression of Foxa2, a transcription factor critical for regulating expression of hepatic gluconeogenic genes during fasting.
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PMID:C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. 1644 Mar 69

Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane. We previously reported that overexpression of integrin beta1 subunit imposed a growth inhibitory effect on the hepatocellular carcinoma cell line SMMC-7721 through transcriptional activation of p21(WAF1/CIP1) gene. In this study, we further determined the molecular mechanisms underlying p21(WAF1/CIP1) expression induced by integrin beta1 overexpression. We report herein that overexpression of integrin beta1 subunit upregulates p21(WAF1/Cip1) transcription through a p53-independent pathway. The overexpressed integrin beta1 activates the p21(WAF1/Cip1) promoter through the Sp1/Sp3 sites and makes more transcription factor Sp1 recruited to the proximal p21 promoter region. In addition, it makes the acetylation value of histone proteins increased across some parts of the p21(WAF1/Cip1) gene, especially in the promoter region. The transcriptional co-activator p300, which possesses intrinsic histone acetyltransferase, was found to be involved in the integrin beta1-mediated histone acetylation and p21 transcriptional activation. Therefore, these findings presented the mechanisms by which integrin beta1 induced the elevated p21 expression in hepatic cancer cells.
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PMID:Increased expression of integrin beta1 subunit enhances p21WAF1/Cip1 transcription through the Sp1 sites and p300-mediated histone acetylation in human hepatocellular carcinoma cells. 1721 49

Protein acetylation is increasingly recognized as an important post-translational modification. Although a lot of protein acetyltransferases have been identified, a few putative acetyltransferases are yet to be studied. In this study, we identified a novel protein acetyltransferase, Patt1, which belongs to GNAT family. Patt1 exhibited histone acetyltransferase activity and auto-acetylation activity. Deletion and mutation analysis of the predicted acetyltransferase domain in Patt1 showed that the conserved Glu139 was an important residue for its protein acetyltransferase activity. Furthermore, we found that Patt1 was highly expressed in liver and significantly downregulated in hepatocellular carcinoma tissues. In addition, we showed that overexpression of Patt1 enhanced the apoptosis of hepatoma cells dependent on its acetyltransferase activity, whereas knockdown of Patt1 significantly protected Chang liver cells from apoptosis. These data suggest that Patt1 might be involved in the development of hepatocellular carcinoma, and could be served as a potential therapy target for hepatocellular carcinoma.
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PMID:Patt1, a novel protein acetyltransferase that is highly expressed in liver and downregulated in hepatocellular carcinoma, enhances apoptosis of hepatoma cells. 1969 38


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