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  • 1
    Keywords: GENES ; GENOME ; transcription ; DIFFERENTIATION ; CHROMATIN ; DNA methylation ; STEM-CELLS ; REGULATORS ; HYPOMETHYLATION ; LONG NONCODING RNA
    Abstract: Epigenetic aberrations are recognized as an early and common event during carcinogenesis. This provides a strong rationale for a therapeutic intervention at the epigenetic level. Current epigenetically active drugs, however, lack specificity for particular genomic loci. Better processes for a more targeted manipulation of the cancer epigenome are needed. One option could be the ability of long noncoding RNAs (lncRNAs) to recruit the chromatin modification complexes to particular genomic loci. In consequence, epigenetic variations would not be stochastic but controlled by a directed programme, through which specific groups of genes are regulated by promoter methylation and(or) histone marks, even if located on different chromosomes. lncRNAs are known to be functionally involved in cell fate specification and carcinogenesis. Depleting lncRNAs with oncogenic potential or replacing scarce molecules with tumor suppressor activity could therefore be employed for a specific reprogramming of the epigenome of cancer cells. Apart from the targeted manner and thus specificity, the mode of action by itself could be an advantage of lncRNA-associated therapy. Similar to what happens naturally during cell fate decisions, the whole developmental programme of a cell or particular parts of it could be reset. In consideration of the early onset of epigenetic aberrations, such an approach could even be useful for cancer prevention. (c) 2011 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 22045689
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  • 2
    Keywords: COLORECTAL-CANCER ; DNA methylation ; STEM-CELLS ; GASTRIC-CANCER ; FACTOR-I ; WNT SIGNALING PATHWAY ; PROMOTER HYPERMETHYLATION ; TUMOR-SUPPRESSOR GENES ; CPG ISLAND METHYLATION ; SFRP GENES
    Abstract: BACKGROUND: The Wnt/beta-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/beta-catenin pathway inhibitor genes - CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 - in the cell lines EHEB and MEC-1 as well as patient samples. METHODS: Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and beta-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. RESULTS: For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2 -deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/beta-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2 -deoxycytidine caused accumulation of beta-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with beta-catenin and thus demonstrating its epigenetically regulated inhibition effect. CONCLUSIONS: The results suggest an epigenetic silencing mechanism of the Wnt/beta-catenin pathway inhibitor genes in CLL. Hypermethylation and silencing of functionally related genes may not be completely stochastic but result from the tumour epigenome reprogramming orchestrated by Polycomb-group repressive complexes. The data are of interest in the context of epigenetic-based therapy.
    Type of Publication: Journal article published
    PubMed ID: 22672427
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