Multiple new phenotypes induced in and 3T3 cells treated with 5-azacytidine

Taylor, Shirley M.; Jones, Peter A.

doi:10.1016/0092-8674(79)90317-9

Cited by 1,075 publications

(657 citation statements)

References 14 publications

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“…5aza-dC is widely used to reactivate the expression of genes silenced by methylation (Heller et al, 2010). It has also been shown to induce cellular differentiation (Taylor and Jones, 1979;Momparler et al, 1985). Genes that were significantly upregulated in at least four cell lines after treatment were considered to be hypermethylated and were mapped onto the four DTs (Figure 4).…”

Section: Go Analysismentioning

confidence: 99%

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

2011

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Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns (that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors.

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Section: Go Analysismentioning

confidence: 99%

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

2011

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“…However, it may have a role in sensitising tumours to other anticancer therapies by causing re-expression of genes involved in drug sensitivity (Plumb et al, 2000). In vitro the differentiating effect of decitabine in cultured fibroblasts has a narrow dose window with a loss of action at high doses possibly caused by cytotoxicity as a result of its incorporation into DNA (Taylor and Jones, 1979). It may, therefore, be more appropriate to use demethylating agents at concentrations below the maximally tolerated dose, but still at a level where they are known to cause demethylation and induce gene re-expression.…”

Section: Overcoming Epigenetic Resistance Mechanismsmentioning

confidence: 99%

Epigenetics as a mechanism driving polygenic clinical drug resistance

Glasspool¹,

Teodoridis²,

Brown³

2006

Br J Cancer

210

166

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Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such ‘one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance.

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“…When cultured in vitro, hMSC readily differentiate into adipocytes, osteoblasts or chondrocytes under appropriate conditions [6]. 5-Azacytidine interferes with DNA methylation and was shown to induce mouse 10T1/2 fibroblasts to differentiate into skeletal myoblasts by reactivation of the transcription of silenced genes including MyoD [7,8]. After treatment with the drug, immortalized murine bone marrow-derived stromal cells differentiated into cardiomyocytes of various excitation properties [9] similar to the results obtained in cardiomyocytes derived from multipotent embryonic stem cells [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

et al. 2006

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Previously, mouse bone marrow-derived stem cells (MSC) treated with the unspecific DNA methyltransferase inhibitor 5-azacytidine were reported to differentiate into cardiomyocytes. The aim of the present study was to investigate the efficiency of a similar differentiation strategy in human mononuclear cells obtained from healthy bone marrow donors. After 1-3 passages, cultures were exposed for 24 h to 5-azacytidine (3 µM) followed by 6 weeks of further culture. Drug treatment did not induce expression of myogenic marker MyoD or cardiac markers Nkx2.5 and GATA-4 and did not yield beating cells during follow-up. In patch clamp experiments, approximately 10-15% of treated and untreated cells exhibited L-type Ca 2+ currents. Almost all cells showed outwardly rectifying K + currents of rapid or slow activation kinetics. Mean current amplitude at +60 mV doubled after 6 weeks of treatment compared with time-matched controls. Membrane capacitance of treated cells was significantly larger than in controls 2 weeks after treatment and remained high after 6 weeks. Expression levels of mRNAs for the K + channels Kv1.1, Kv1.5, Kv2.1, Kv4.3 and KCNMA1 and for the Ca 2+ channel Ca v 1.2 were not affected by 5-azacytidine. Treatment with potassium channel blockers tetraethylammonium and clofilium at concentrations shown previously to inhibit rapid or slowly activating K + currents of hMSC inhibited proliferation of these cells. Our results suggest that despite the absence of differentiation of hMSC into cardiomyocytes, treatment with 5-azacytidine caused profound changes in current density.Cell Research (2006) 16:949-960.

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Multiple new phenotypes induced in and 3T3 cells treated with 5-azacytidine

Cited by 1,075 publications

References 14 publications

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

Epigenetics as a mechanism driving polygenic clinical drug resistance

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

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