Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5' flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms.
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PMID:MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer. 1672 89

HOXA5 is a member of the HOX gene family, which is known to play key roles during embryonic development and in differentiation of adult cells. In addition, HOXA5 has been implicated as a tumour suppressor in breast cancer and shown to transactivate the p53 gene. CpG island methylation is a common mechanism of gene inactivation in tumour cells, but is rarely involved in control of cell-type-specific (CTS) expression in normal cells. However, here we demonstrate that HOXA5 is one of a small number of genes whose CTS expression pattern is controlled by CTS CpG island methylation in normal cells. Furthermore, chromatin immunoprecipitation analysis identified novel patterns of histone modifications associated with DNA methylation of HOXA5. High levels of methylation of histone residues (lysine 9 and 36 of histone H3) previously associated with transcriptional repression were present in the unmethylated, actively transcribing state, and were then reduced following DNA methylation and gene inactivation. Alterations to the normal patterns of HOXA5 gene methylation were also observed in tumour cells. Quantitative analysis of HOXA5 methylation identified the presence of limited methylation in all of the breast, lung and ovarian tumours examined. However, methylation levels in these three tumour types were nearly always low and comparable with that detected in the corresponding normal tissue. In contrast, acute myeloid leukaemia (AML) samples frequently (60% of samples) exhibited very high methylation levels, far greater than that seen in normal haematopoietic cells, suggesting a role for hypermethylation of HOXA5 in the development of AML, consistent with its previously identified role in haematopoietic differentiation.
Carcinogenesis 2007 Feb
PMID:HOXA5 is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia. 1686 Dec 63

Dimethylated histone H3 lysine 9 (H3K9me2) is a critical epigenetic mark for gene repression and silencing and plays an essential role in embryogenesis and carcinogenesis. Here, we investigated the effects of hypoxic stress on H3K9me2 at both global and gene-specific level. We found that hypoxia increased global H3K9me2 in several mammalian cell lines. This hypoxia-induced H3K9me2 was temporally correlated with an increase in histone methyltransferase G9a protein and enzyme activity. The increase in H3K9me2 was significantly mitigated in G9a-/- mouse embryonic stem cells following hypoxia challenge, indicating that G9a was involved in the hypoxia-induced H3K9me2. In addition to the activation of G9a, our results also indicated that hypoxia increased H3K9me2 by inhibiting H3K9 demethylation processes. Hypoxic mimetics, such as deferoxamine and dimethyloxalylglycine, were also found to increase H3K9me2 as well as G9a protein and activity. Finally, hypoxia increased H3K9me2 in the promoter regions of the Mlh1 and Dhfr genes, and these increases temporally correlated with the repression of these genes. Collectively, these results indicate that G9a plays an important role in the hypoxia-induced H3K9me2, which would inhibit the expression of several genes that would likely lead to solid tumor progression.
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PMID:Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. 1698 42

Previously we identified circulating autoantibodies in high titre in the serum of a patient with biopsy-proven discoid lupus erythematosus reactive to serine/threonine phosphoepitopes of the novel mitotic chromosomal autoantigen we named MCA1. MCA1-reactive antibodies have subsequently been demonstrated to bind to the modified histone H3 (H3K9me3S10ph). In this study we utilised Epstein Barr virus (EBV) infection of peripheral blood mononuclear cells collected from this patient to immortalise B-lymphocytes producing MCA1-reactive antibodies. We found MCA1-reactive antibody production by the EBV-immortalised B-lymphocytes unstable in culture. We discuss the possibilities of producing MCA-1-reactive reagents through protein engineering methods (variable or complementarity-determining region grafting) and to modulate antibody affinity through library technologies (such as phage, yeast or ribosome display). Clinical studies have shown that carcinogenesis is most often linked to the development of proliferative abnormalities and proliferative activity has prognostic significance in a variety of human tumours. Here we demonstrate the potential utility of antibodies reactive to H3K9me3S10ph (MCA1), which is only detected on mitotic chromatin, as a marker for cell proliferation in FACS analysis, tissue section staining and in determination of mitotic indices.
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PMID:MCA1 detection of histone H3 serine 10 phosphorylation, a novel biomarker for determination of mitotic indices. 1706 38

The methyl-deficient model of endogenous hepatocarcinogenesis in rodents is unique in that dietary omission rather than the addition of chemical carcinogens leads to tumor formation. Thus, the biochemical and molecular events predisposing to cancer in this model result from chronic metabolic stress and provide an ideal model system to study progressive alterations that occur during carcinogenesis. Moreover, epigenetic alterations imposed by this diet are believed to be 1 of the main mechanisms responsible for malignant transformation of rat liver cells. In this study we examined the changes in global histone modification patterns in liver during hepatocarcinogenesis induced by methyl deficiency. Feeding animals the methyl-deficient diet (MDD) led to progressive loss of histone H4 lysine 20 trimethylation (H4K20me3), H3 lysine 9 trimethylation (H3K9me3), and histone H3 lysine 9 (H3K9ac) and histone H4 lysine 16 (H4K16ac) acetylation. A considerable decrease of H4K20me3 and H3K9ac was also detected in liver tumors induced by MDD. In contrast, liver tumors displayed an increase in H3K9me3 and H4K16ac. To determine the possible mechanism of alterations of histone modifications, we analyzed the expression of histone-modifying enzymes in liver during hepatocarcinogenesis. The expression of Suv4-20h2 and RIZ1 histone methyltransferases (HMTs) steadily decreased along with the development of liver tumors and reached its lowest level in tumor tissue, whereas the expression of Suv39-h1 HMT and histone acetyltransferase 1 (HAT1) substantially increased in tumors. These results illustrate the complexity and importance of histone modification changes in the etiology of hepatocarcinogenesis induced by MDD.
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PMID:Methyl deficiency, alterations in global histone modifications, and carcinogenesis. 1718 29

The androgen receptor (AR) plays a key role as a transcriptional factor in prostate development and carcinogenesis. Identification of androgen-regulated genes is essential to elucidate the AR pathophysiology in prostate cancer. Here, we identified androgen target genes that are directly regulated by AR in LNCaP cells, by combining chromatin immunoprecipitation (ChIP) with tiling microarrays (ChIP-chip). ChIP-enriched or control DNAs from the cells treated with R1881 were hybridized with the ENCODE array, in which a set of regions representing approximately 1% of the whole genome. We chose 10 bona fide AR-binding sites (ARBSs) (P<1e-5) and validated their significant AR recruitment ligand dependently. Eight upregulated genes by R1881 were identified in the vicinity of the ARBSs. Among the upregulated genes, we focused on UGT1A and CDH2 as AR target genes, because the ARBSs close to these genes (in UGT1A distal promoter and CDH2 intron 1) were most significantly associated with acetylated histone H3/H4, RNA polymerase II and p160 family co-activators. Luciferase reporter constructs including those two ARBSs exhibited ligand-dependent transcriptional regulator/enhancer activities. The present study would be powerful to extend our knowledge of the diversity of androgen genetic network and steroid action in prostate cancer cells.
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PMID:Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis. 1729 73

Glutathione-S-transferases (GSTs) are metabolic enzymes that help detoxify and eliminate harmful chemicals. In prostate tumors, expression of GST pi (encoded by GSTP1) is frequently lost because of promoter hypermethylation. Here we analyze the native GSTP1 promoter in cancerous and noncancerous human prostate cells to identify structural features associated with its cancer-related transcriptional silencing. We find that in noncancerous prostate cells (RWPE-1 and PWR-1E) GSTP1 is constitutively expressed, not methylated, highly accessible, bound by transcription factors and associated with histones with activating modifications (histone H3 methylated at lysine 4 and acetylated histones H3 and H4). In contrast, in cancerous prostate cells (LNCaP) GSTP1 is not expressed, extensively methylated, inaccessible, lacks bound transcription factors and is not associated with histones with activating modifications. We do not detect significant levels of histones with repressive modifications (histone H3 methylated at lysine 9 or 27) on GSTP1 in any cell line indicating that they are not associated with cancer-related GSTP1 silencing. Treatment of LNCaP cells with 5-azacytidine restores activating histone modifications on GSTP1 and reactivates transcription. We conclude that, in the process of prostate carcinogenesis, activating histone modifications on GSTP1 are lost and the DNA becomes methylated and inaccessible resulting in transcriptional silencing.
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PMID:Chromatin changes on the GSTP1 promoter associated with its inactivation in prostate cancer. 1741 78

Little is known about early carcinogen-induced protein alterations in mammary epithelium. Detection of early alterations would enhance our understanding of early-stage carcinogenesis. Here, normal human mammary epithelial cells (HMECs) were exposed to dietary and environmental carcinogens [2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP), 4-aminobiphenyl (ABP), benzo[a]pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin] individually or in combination. A phage display library of single-chain variable fragment antibodies was used to screen protein targets altered by the treatment. In combination with matrix-assisted laser desorption time of flight, we identified histone H3 as a target antigen. Although histone H3 total protein remained unchanged in control and treated HMEC, the methylation of lysine 4 was altered. A reduction in mono-methyl histone H3 (Lys 4) was observed in treated HMEC compared with control HMEC. This alteration was shown to be dependent on carcinogen concentration and specific for PhIP and ABP. To characterize potential histone demethylation mechanisms, localization and protein expression patterns of lysine-specific demethylase 1 (LSD1) were analyzed. In control HMEC, LSD1 was present at the nuclear periphery. However, following 72 h carcinogen treatment, LSD1 localized within the nucleus. Within 48 h after treatment, mono-methyl histone H3 (Lys 4) was restored and LSD1 localization was reversed. Protein expression levels of LSD1 were also increased in treated HMEC compared with control HMEC. Our data suggest that the induction of a single enzyme, LSD1, represents an early response to carcinogen exposure, which leads to the demethylation of histone H3 (Lys 4), which, in turn, may influence the expression of multiple genes critical in early-stage mammary carcinogenesis.
Carcinogenesis 2007 Oct
PMID:Carcinogen-induced histone alteration in normal human mammary epithelial cells. 1746 14

Among mediators of oxidative stress, highly reactive secondary aldehydic lipid peroxidation products can initiate the processes of spontaneous mutagenesis and carcinogenesis and can also act as a growth-regulating factors and signaling molecules. We explored whether these aldehydes and histone H3 mRNA levels could serve as biomarkers of malignancy and predictive factor in human brain astrocytomas. Histone H3 mRNA, a biomarker of cellular proliferation, was analyzed by QRT-PCR (TaqMan). Aldehydic lipid peroxidation products were determined as their dinitrophenylhydrazone derivatives in specimens obtained from 26 adult patients with brain astrocytomas. RP-HPLC with diode array detector and MSMS spectrometer were used for the analysis. H3 mRNA, 2-hydroxyhexanal, and 4-hydroxynonenal levels were higher in high-grade astrocytomas compared to low-grade astrocytomas and showed negative correlation with survival. Higher levels of 2-hydroxyhexanal and 4-hydroxynonenal, and lower levels of n-hexanal were associated with poorer patient prognosis. Our data suggest that tissue concentrations of aldehydic lipid peroxidation products can assist grading and predicting the clinical outcome in patients with astrocytic brain tumors. Possibly, this parameter will enhance optimal selection of patients for individualized treatment protocols, tailored to unique biochemical and molecular profile of the tumor.
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PMID:Aldehydic lipid peroxidation products in human brain astrocytomas. 1748 52

Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi-step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol-17beta (E(2))-induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E(2)-induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E(2)-induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyperplasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE-1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after six weeks of E(2)-treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after twelve weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E(2) and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E(2)-induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process.
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PMID:Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications and aberrant microRNA expression. 1770 64


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