Ballestar E, Esteller MThe impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis 23: 1103-1109

Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, 28029 Madrid, Spain.
Carcinogenesis (Impact Factor: 5.33). 08/2002; 23(7):1103-9. DOI: 10.1093/carcin/23.7.1103
Source: PubMed


For decades, chromatin was considered to be an inert structure whose only role was the compacting and confining of DNA inside the eukaryotic nucleus. However, tremendous progress in this field over the last 10 years has dramatically elevated chromatin to a key position in the control of gene activity. Its role in mediating the transformation of a normal cell into a malignant state is particularly interesting. On one side of this story there is the discovery that aberrant methylation patterns in an increasing number of tumour suppressor and DNA repair genes determine carcinogenetic transformation; while on the other side, there is the existence of a series of methyl-DNA binding activities that recruit co-repressor complexes and modify the structure of the chromatin to produce a transcriptionally silenced state. Although this field has seen rapid progress in recent years, detailed mechanisms by which this machinery modifies chromatin structure to its appropriate state and the specific targeting of repressor complexes have yet to be resolved. In this review we present the models of how repressor complexes may modify chromatin structure and mediate silencing of tumour suppressor and DNA repair genes.

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    • "HDAC1 and DNMT1 contribute to gene silencing through recruiting transcriptional repressors to promoter regions [33]–[35] and work together to suppress gene expression [24], [36]. Our data suggest that HDAC and DNMT activities cooperatively silence RGS10 (Fig. 4C). "
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    ABSTRACT: RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.
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    • "Processes like transformation, development, genomic stability, and programmed cell death are commonly altered processes in cancer cells [5]. In addition, the maintenance or silencing of chromatin may be at the center of processes leading to the aging of cells and development of cancer [25]. These processes appear in our list of the most significant enrichments. "
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    ABSTRACT: Array comparative genomic hybridization (aCGH) technology provides high-resolution measurements of DNA aberrations at tens of thousands of locations distributed throughout the genome. These genomic aberrations cause alterations in gene expression patterns which, in turn, are a common cause for emergence of cancer. However, like all other microarray technologies, the obtained measurement data is noisy. In addition to the measurement noise, the heterogeneity of biological samples and cancer cells add biological noise and it also needs to be taken into account. To infer reliable results, analysis of aCGH data requires that different sources of uncertainty are carefully considered. We present an analysis framework that can be used to find reliable estimates of genomic aberrations that are frequent throughout a set of aCGH data. These commonly aberrant segments of DNA and the genes that reside in them, are key factors in understanding cancer. We demonstrate our framework by applying it to a set of aCGH data obtained from two different types of cancer. We also investigate what biological processes are affected by the mutations uncovered by our analysis of these cancer types using gene ontology enrichment. Based on this enrichment analysis, our framework reliably finds common aberrations in aCGH data.
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    • "Dickkopf-1 CpG island methylation status was determined by polymerase chain reaction (PCR) analysis of bisulfite-modified genomic DNA using two procedures: bisulfite genomic sequencing (BGS) and methylation-specific PCR (Herman et al, 1996; Ballestar & Esteller, 2002; Fraga et al, 2005). We analysed the methylation status of 18 CpG sites in the DKK1 promoter and tentatively numbered them from 5¢–3¢ ( "
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    ABSTRACT: The Dickkopf-1 (DKK1) gene product is an extracellular Wnt inhibitor. Hypermethylation of the DKK1 promoter results in transcriptional silencing and may play an important role in cancer development. Here, we investigated hypermethylation of the DKK1 promoter in patients with acute myeloid leukaemia (AML), especially core-binding factor (CBF) leukaemia. The methylation status of DKK1 was analysed using methylation-specific polymerase chain reaction in 47 patients with AML. DKK1 methylation was found in 14 (29.8%) patients, and more frequently in those with CBF leukaemia (6 of 12 patients), than in those with acute promyelocytic leukaemia (APL) (0 of 6 patients) (P = 0.03). In contrast, Wnt inhibitory factor-1 methylation was found in APL (4 of 6 patients) but not in CBF leukaemia (0 of 12 patients) (P = 0.001). Multivariate analyses suggested that DKK1 methylation was a risk factor for poorer overall survival. Sequential analysis using four paired samples obtained at diagnosis and relapse suggested that DKK1 methylation was involved in the progression of leukaemia. Therefore, DKK1 methylation may be involved in leukaemogenesis, especially in CBF leukaemia, and may be a useful prognostic marker in AML.
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