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  • GENE-EXPRESSION  (20)
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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; BLOOD ; CELL ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; LINES ; DNA ; MECHANISM ; CELL-LINES ; ACID ; TRANSPORT ; CHROMATIN ; chromatin remodeling ; gene expression ; CELL-DEATH ; PROMOTER ; CELL-LINE ; leukemia ; LINE ; DNA methylation ; acetylation ; HISTONE DEACETYLASE ; histone deacetylase inhibitor ; METHYLATION ; HYPERMETHYLATION ; NORMAL CYTOGENETICS ; TUMOR-SUPPRESSOR ; METHYLTRANSFERASE ; REARRANGEMENT ; TRANSPORTER ; ADULT PATIENTS ; cell death ; SUPPRESSOR ; PROMOTER HYPERMETHYLATION ; USA ; DECITABINE ; H4 ; GROUP-B ; DNA-METHYLATION ; response ; tumor suppressor ; epigenetic ; ABERRANT METHYLATION ; PARTIAL TANDEM DUPLICATION ; ALL-1
    Abstract: Posttranslationally modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the mixed lineage leukemia partial tandem duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT-, P =.02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P =.003). In MLL-PTD+ cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein-SMCT1-short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD+ AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression
    Type of Publication: Journal article published
    PubMed ID: 18566324
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  • 2
    Keywords: CANCER ; EXPRESSION ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; human ; QUANTIFICATION ; SYSTEM ; SYSTEMS ; TOOL ; DISEASE ; DISEASES ; GENE ; GENE-EXPRESSION ; SAMPLE ; SAMPLES ; TISSUE ; DNA ; MECHANISM ; TISSUES ; mechanisms ; BIOLOGY ; SEQUENCE ; SEQUENCES ; DISORDER ; SCHIZOPHRENIA ; NEOPLASIA ; PATTERNS ; gene expression ; DISRUPTION ; genetics ; REPRODUCIBILITY ; EFFICACY ; DNA methylation ; INSTABILITY ; UNITED-STATES ; ELECTROPHORESIS ; sensitivity ; METHYLATION ; GENOMIC INSTABILITY ; HYPERMETHYLATION ; INHIBITORS ; molecular biology ; HUMAN CANCER ; 5-methylcytosine ; cell proliferation ; CPG ISLANDS ; TECHNOLOGY ; microfluidics ; USA ; ACCURATE ; CANCER GENETICS ; epigenetic ; STATE ; Genetic ; ISLANDS ; RESTRICTION ; DNA/analysis/chemistry/genetics *DNA Methylation DNA Restriction Enzymes Electrophoresis,Polyacrylam ; METHYLATION INHIBITOR
    Abstract: DNA methylation is the best-studied epigenetic modification, and in mammals it describes the conversion of cytosine to 5-methylcytosine in the context of CpG dinucleotides. In recent years, it has become evident that epigenetic mechanisms are severely disrupted in human neoplasia, and evidence suggests that alterations of DNA methylation patterns may be an integral mechanism in the etiology of other diseases such as bipolar disorder and schizophrenia. The main effect of altered DNA methylation is the disruption of normal patterns of gene expression through genomic instability and hypermethylation of CpG islands, which together could lead to uncontrolled cell proliferation. DNA methylation can be reversed through pharmacological intervention via the systemic administration of DNA methylation inhibitors. Thus, the ability to accurately quantify DNA methylation levels in genomic sequences is a prerequisite to assess not only treatment efficacy, but also the effect of the DNA methylation inhibitors on bystander tissues. Several methods are currently available for the analysis of DNA methylation. Nonetheless, accurate and reproducible quantification of DNA methylation remains challenging. Here, we describe Bio-COBRA, a modified protocol for combined bisulfite restriction analysis (COBRA) that incorporates an electrophoresis step in microfluidics chips. Microfluidics technology involves the handling of small amounts of liquid in miniaturized systems. Bio-COBRA provides a platform for the rapid and quantitative assessment of DNA methylation patterns in large sample sets. Its sensitivity and reproducibility also make it an excellent tool for the analysis of DNA methylation in clinical samples
    Type of Publication: Journal article published
    PubMed ID: 18987820
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  • 3
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; COMBINATION ; MODEL ; VITRO ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; TISSUE ; LINES ; DNA ; CARCINOGENESIS ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; genetics ; DNA methylation ; inactivation ; PCR ; REGION ; TRANSFORMATION ; EPITHELIAL-CELLS ; CARCINOMAS ; NETHERLANDS ; histone deacetylase inhibitor ; METHYLATION ; HYPERMETHYLATION ; ESTRADIOL ; PATTERN ; SCIENCE ; CPG ISLANDS ; ESTROGEN ; 17-BETA-ESTRADIOL ; EPIGENETIC CHANGES ; MESENCHYMAL TRANSITION ; Genetic ; heregulin ; Cell transformation ; ERBB RECEPTOR FAMILY ; HISTONE-DEACETYLASE INHIBITORS ; Neuregulin
    Abstract: Epigenetic inactivation of genes by DNA hypermethylation plays an important role in carcinogenesis An in vitro model of human breast epithelial cell transformation was used to study epigenetic changes induced by estradiol during the neoplastic process Different stages of tumor initiation and progression are represented in this model being MCF-10F the normal stage; trMCF cells, the transformed stage, bsMCF cells, the invasive stage and, caMCF cells, the tumor stage Global methylation studies by restriction landmark genomic scanning (RLGS) showed an increased DNA methylation during the in the invasive and tumor stages Expression studies showed that NRG1 (neuregulin 1), CSS3 (chondroitin sulfate synthase 3) and SNIP (SNAP-25-interacting protein) were downregulated in the invasive and tumor cells. The transformed cells showed low expression of STXBP6(amysin)compared to the parental cells MCF-10F The treatment of these cells with the demethylating agent 5-aza-dC alone or in combination with the histone deacetylase inhibitor trichostatin increased the expression of NRG1, STXBP6, CSS3 and SNIP confirming that DNA methylation plays an Important role in the regulation of the expression of these genes The NRG1 exon 1 has a region located between -136 and +79 (considering +1, the translational initiation site) rich in CpG sites that was analyzed by methylation specific PCR (MSP) NRG1 exon 1 showed progressive changes in the methylation pattern associated with the progression of the neoplastic process in this model; NRG1 exon 1 was unmethylated in MCF-10F and trMCF cells, becoming hypermethylated in the invasive (bsMCF) and tumor (caMCF) stages Studies of human breast tissue samples showed that NRG1 exon 1 was partially methylated in 14 out of 17 (82.4%) invasive carcinomas although it was unmethylated in normal tissues (8 out of 10 normal breast tissue samples) Furthermore, NRG1 exon 1 was partially methylated in 9 out of 14(64.3%) morphologically normal tissue samples adjacent to invasive carcinomas. (C) 2010 Elsevier B V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20193695
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  • 4
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; IN-VIVO ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; MECHANISM ; INDUCTION ; CYCLE ; ACID ; DNA methylation ; POLYPHENOLS ; RECEPTORS ; chemoprevention ; histone deacetylase inhibitor ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HYPERMETHYLATION ; RETINOIC ACID ; HYPOMETHYLATION ; INHIBITORS ; SUPPRESSOR GENES ; HISTONE ACETYLATION ; high-throughput analysis ; CPG-ISLAND METHYLATION ; chemopreventive agents ; TUMOR-SUPPRESSOR GENES ; epigenetic ; histone modifications ; DNA METHYLTRANSFERASE INHIBITORS ; chromatin modifications ; HISTONE METHYLATION ; ABERRANT CRYPT FORMATION ; DNA methyltransferase (DNMT) ; epigenomic ; GREEN TEA POLYPHENOLS ; histone acetyl transferase (HAT) ; histone deacetylase (HDAC) ; NORDIHYDROGUAIARETIC ACID NDGA ; sirtuins ; SMALL-MOLECULE ACTIVATORS
    Abstract: The term "epigenetics" refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies. The present review will give a comprehensive overview of the current literature on chemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histone acetylation and methylation, and microRNAs, both in vitro and in rodent and human studies, taking into consideration specific mechanisms of action, target sites, concentrations, methods used for analysis, and outcome. Chemopreventive agents with reported mechanisms targeting the epigenome include micronutrients (folate, selenium, retinoic acid, Vit. E), butyrate, polyphenols (from green tea, apples, coffee, and other dietary sources), genistein and soy isoflavones, parthenolide, curcumin, ellagitannin, indol-3-carbinol (I3C) and diindolylmethane (DIM), mahanine, nordihydroguaiaretic acid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables (sulforaphane, phenylethyl isothiocyanate (PEITC), phenylhexyl isothiocyanate (PHI), diallyldisulfide (DADS), allyl mercaptan (AM)), antibiotics (mithramycin A, apicidin), pharmacological agents (celecoxib, DFMO, 5-aza-2'-deoxycytidine and zebularine), compounds affecting sirtuin activity (resveratrol, dihydrocoumarin, cambinol), inhibitors of histone acetyl transferases (anacardic acid, garcinol, ursodeoxycholic acid), and relatively unexplored modulators of histone lysine methylation (chaetocin, polyamine analogues, n-3 polyunsaturated fatty acids). Their effects on global DNA methylation, tumor suppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated during carcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transduction mediated by nuclear receptors and transcription factors such as NF-kappaB, cell cycle progression, cellular differentiation, apoptosis induction, senescence and others. In vivo studies that demonstrate the functional relevance of epigenetic mechanisms for chemopreventive efficacy are still limited. Future research will need to identify best strategies for chemopreventive intervention, taking into account the importance of epigenetic mechanisms for gene regulation.
    Type of Publication: Journal article published
    PubMed ID: 21158707
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  • 5
    Keywords: CANCER ; PATHWAY ; GENE-EXPRESSION ; TRANSCRIPTION FACTOR ; PROGRESSION ; chemotherapy ; EMBRYONIC STEM-CELLS ; PROMOTER HYPERMETHYLATION ; AML ; TUMOR-NECROSIS
    Abstract: BACKGROUND: Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. METHODS: We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. RESULTS: We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. CONCLUSIONS: Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.
    Type of Publication: Journal article published
    PubMed ID: 24944583
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  • 6
    Keywords: IN-VITRO ; GENE-EXPRESSION ; DNA methylation ; MELANOMA ; SQUAMOUS-CELL CARCINOMA ; HEAD ; GLIOBLASTOMA ; CHONDROITIN SULFATE PROTEOGLYCAN ; ANTIBODY-BASED IMMUNOTHERAPY ; NG2 EXPRESSION
    Abstract: Proteoglycans are often overexpressed in tumors and can be found on several normal and neoplastic stem cells. In this study, we analyzed in-depth the role of CSPG4 in head and neck squamous cell carcinomas (HNSCC). Analysis of CSPG4 in a homogeneous study sample of HPV-negative stage IVa HNSCCs revealed overexpression of protein and mRNA levels in a subgroup of HNSCC tumors and a significant association of high CSPG4 protein levels with poor survival. This could be validated in three publicly available microarray datasets. As a potential cause for upregulated CSPG4 expression, we identified DNA hypomethylation in a CpG-island of the promoter region. Accordingly, we found an inverse correlation of methylation and patient outcome. Finally, CSPG4 re-expression was achieved by demethylating treatment of highly methylated HNSCC cell lines establishing a direct link between methylation and CSPG4 expression. In conclusion, we identified CSPG4 as a novel biomarker in HNSCC on several biological levels and established a causative link between DNA methylation and CSPG4 protein and mRNA expression.
    Type of Publication: Journal article published
    PubMed ID: 24740185
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  • 7
    Keywords: GENE-EXPRESSION ; EPITHELIAL-CELLS ; TUMOR-SUPPRESSOR ; MESSENGER-RNAS ; epigenetic regulation ; ANDROGEN-RECEPTOR ; LONG-NONCODING-RNA ; POTENTIAL THERAPEUTIC TARGET ; GENOMIC ANALYSES REVEAL ; SWI/SNF COMPLEX
    Abstract: Prostate cancer (PCa) is the second most common cause of cancer-related deaths in men. Despite advances in the characterization of genomic and epigenetic aberrations contributing to PCa, the etiology of PCa is still far from being understood. Research over the past decade demonstrated the role of long non-coding RNAs (lncRNAs) in deregulation of target genes mainly through epigenetic mechanisms. In PCa, evidence accumulated that hundreds of lncRNAs are dysregulated. Functional analyses revealed their contribution to prostate carcinogenesis by targeting relevant pathways and gene regulation mechanisms including PTEN/AKT and androgen receptor signaling as well as chromatin remodeling complexes. Here we summarize our current knowledge on the roles of lncRNAs in PCa and their potential use as biomarkers for aggressive PCa and as novel therapeutic targets.
    Type of Publication: Journal article published
    PubMed ID: 25153594
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  • 8
    Keywords: TYROSINE KINASE ; GENE-EXPRESSION ; TRANSGENIC MICE ; IDENTIFICATION ; PROMOTER ; leukemia ; PATHOGENESIS ; NPM-ALK ; HODGKIN LYMPHOMA ; MICRORNA-155
    Abstract: Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+) ). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-) ), which is characterized by a worse prognosis. We found that ALCL ALK(-) , in contrast to ALCL ALK(+) , lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPbeta and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPbeta and SOCS1. In murine engraftment models of ALCL ALK(-) , we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPbeta target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Publication: Journal article published
    PubMed ID: 25820993
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  • 9
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; VITRO ; SYSTEM ; GENE-EXPRESSION ; PROTEIN ; transcription ; DIFFERENTIATION ; PATIENT ; DNA ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; BINDING ; CELL-LINES ; DOWN-REGULATION ; ALPHA ; TARGET ; PROMOTER ; CELL-LINE ; leukemia ; DNA methylation ; REGION ; PREDICTION ; TARGETS ; protein expression ; C/EBP-ALPHA ; BINDING PROTEIN ; ONCOLOGY ; RE ; LEVEL ; HUMAN CANCER-CELLS ; USA ; LOSSES ; PROMOTER REGION ; cancer research ; valproic acid ; SMALL RNAS ; UPSTREAM ; DNA-METHYLATION ; block ; modification ; UNTRANSLATED REGION ; epigenetic ; DOWN-MODULATION ; MICRORNA GENE
    Abstract: Functional loss of CCAAT/enhancer binding protein alpha (C/ EBP alpha), a master regulatory transcription factor in the hematopoietic system, can result in a differentiation block in granulopoiesis and thus contribute to leukemic transformation. Here, we show the effect of epigenetic aberrations in regulating C/EBP alpha expression in acute myeloid leukemia (AML). Comprehensive DNA methylation analyses of the CpG island of C/EBP alpha identified a densely methylated upstream promoter region in 51% of AML, patients. Aberrant DNA methylation was strongly associated with two generally prognostically favorable cytogenetic subgroups: inv(16) and t(15;17). Surprisingly, while epigenetic treatment increased C/EBP alpha mRNA levels in vitro, C/EBP alpha protein levels decreased. Using a computational microRNA (miRNA) prediction approach and functional studies, we show that C/EBP alpha mRNA is a target for miRNA-124a. This miRNA is frequently silenced by epigenetic mechanisms in leukemia cell lines, becomes up-regulated after epigenetic treatment, and targets the C/EBP alpha 3' untranslated region. In this way, C/EBP alpha protein expression is reduced in a posttranscriptional manner. Our results indicate that epigenetic alterations of C/EBP alpha are a frequent event in AML and that epigenetic treatment can result in down-regulation of a key hematopoietic transcription factor
    Type of Publication: Journal article published
    PubMed ID: 18451139
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  • 10
    Keywords: CELLS ; EXPRESSION ; CELL ; human ; NETWORKS ; SITE ; SITES ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; RNA ; transcription ; LINES ; MECHANISM ; mechanisms ; IDENTIFICATION ; PATTERNS ; gene expression ; microarrays ; PROMOTER ; PROMOTERS ; genetics ; HUMAN GENOME ; HUMAN GENES ; METHYLATION ; heredity ; PATTERN ; GENOME-WIDE ANALYSIS ; ARRAY ; genomics ; RESOURCE ; analysis ; CHIP ; USA ; microbiology ; ENGLAND ; biotechnology ; PLATFORM ; BREAST-CANCER CELLS ; synthesis ; STATE ; GENOME-WIDE ; ESTROGEN-RECEPTOR-ALPHA ; TRANSCRIPTION INITIATION
    Abstract: Background: Independent lines of evidence suggested that a large fraction of human genes possess multiple promoters driving gene expression from distinct transcription start sites. Understanding which promoter is employed in which cellular context is required to unravel gene regulatory networks within the cell. Results: We have developed a custom microarray platform that tiles roughly 35,000 alternative putative promoters from nearly 7,000 genes in the human genome. To demonstrate the utility of this array platform, we have analyzed the patterns of promoter usage in 17 beta-estradiol (E2)-treated and untreated MCF7 cells and show widespread usage of alternative promoters. Most intriguingly, we show that the downstream promoter in E2-sensitive multiple promoter genes tends to be very close to the 3'-terminus of the gene, suggesting exotic mechanisms of expression regulation in these genes. Conclusion: The usage of alternative promoters greatly multiplies the transcriptional complexity available within the human genome. The fact that many of these promoters are incapable of driving the synthesis of a meaningful protein-encoding transcript further complicates the story
    Type of Publication: Journal article published
    PubMed ID: 18655706
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