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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data comparing azacitidine and decitabine in non-small cell lung cancer lines

ABSTRACT: Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8M-bM-^@M-^S10.5 M-BM-5M), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 M-BM-5M). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis. A549 and H1299 cells were treated with a dose range (0.3M-bM-^@M-^S3.0 M-NM-

ORGANISM(S): Homo sapiens

SUBMITTER: Helen Brady

PROVIDER: E-GEOD-29077 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data comparing azacitidine and decitabine in non-small cell lung cancer lines

Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8–10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.

2011-05-05 | GSE29077 | GEO

microRNA expression signatures in colorectal cancer cell lines with demethylating treatment

Project description:To screen for epigenetically silenced miRNAs, wecarried out miRNA microarray analysis in three colorectal cancer (CRC) cell lines (HCT116, DLD-1 and RKO) treated with or without 5-aza-2'-deoxycytidine (aza). HCT116 and RKO cells were also treated with aza plus 4-phenylbutyric acid (PBA). In addition, we analyzed HCT116 cells in which the DNA methyltransferase genes DNMT1 and DNMT3B were genetically disrupted (double knockout; DKO cells), thereby abrogating DNA methylation. Expression of a majority of miRNAs was downregulated in all three CRC cell lines tested, as compared to normal colonic mucosa. DAC treatment upregulated expression of a large number of miRNAs in all three CRC cell lines, and combination treatment with DAC plus PBA induced even greater numbers of miRNAs in CRC cells. The most profound effect on the miRNA expression profile was induced by genetic disruption of DNMT1 and DNMT3B in HCT116 cells. CRC cells were treated with 5-aza-2’-deoxycytidine (aza) or aza plus 4-phenylbutyrate (PBA). Nomal colon RNA was purchased from BioChain. Expression of 470 miRNAs was analyzed using Human miRNA Microarray V1 (G4470A; Agilent technologies, Santa Clara, CA, USA).

2011-07-01 | E-GEOD-29900 | biostudies-arrayexpress

Comparison of DNMT1 inhibitors by methylome profiling identifies unique signature of 5-aza-2'deoxycytidine (expression)

Project description:Dacogen (DAC/ 5-aza-2’deoxycitidine/Aza) is currently used to treat myeloid dysplastic syndrome (MDS) and is in trials for Acute Myeloid Leukaemia (AML) and some solid cancers. As a hypomethylating agent it is thought to act by inhibiting the enzymes which add methyl groups to DNA, chief among them DNMT1. Improved targeting has been hindered by a lack of understanding of the off-target effects following treatment. Both Dacogen and DNMT1 siRNA caused overall hypomethylation in the treated cells, with the latter proving more efficient at demethylation at gene bodies in particular. Amongst the targets experiencing demethylation, some hypomethylated promoters were unique to Dacogen treatment and therefore off-target with respect to the reduction in DNMT1. An unexpected phenomenon almost exclusively caused by DAC treatment was gain in methylation. Our results suggest Dacogen is also having an important effect on methylation unrelated to the inhibition of DNMT1, suggesting further avenues for therapeutic improvements.

2019-07-31 | GSE104360 | GEO

Comparison of DNMT1 inhibitors by methylome profiling identifies unique signature of 5-aza-2'deoxycytidine [methylation]

2019-07-31 | GSE104359 | GEO

Mapping of DNA methylation-sensitive cellular processes in gingival fibroblasts using the DNMT inhibitor decitabine

Project description:Epigenetic changes in DNA methylation are involved in periodontitis pathogenesis and recent studies indicate that DNA methyltransferase (DNMT) inhibitors may protect against bone resorption and disruption of the epithelial barrier. To assess the impact of DNMT inhibition on gingival fibroblasts (GFs), cells were cultured with decitabine (5-aza-2’-deoxycytidine, DAC) for 12 days to induce DNA hypomethylation. Analysis of DAC-induced genes in resting or P. gingivalis-infected GFs identified by RNA sequencing revealed increased expression of CCL20, CCL5, CCL8, CCL13, TNF, IL1A, IL18, IL33, and CSF3, and showed that the most affected processes were related to immune and inflammatory responses. In contrast, the genes downregulated by DAC were associated with extracellular matrix and collagen fibril organization.

2023-01-05 | GSE216757 | GEO

Genes regulated by miR-34b/c and DAC

Project description:We found frequent epigenetic silencing of microRNA-34b/c in human colorectal cancer. Introduction of miR-34b/c into a colorectal cancer cell line induced significant changes in gene expression profile. We also found overlap between the genes downregulated by miR-34b/c and those downregulated by DAC. Keywords: dose response A colorecal cancer cell line HCT116 was transfected with miR-34b or -c precursor or negative control. Also, HCT116 was treated with 5-aza-2'-deoxycytidine (DAC) or mock. Genes up- or downregulated by miR-34b/c and those by DAC was compared.

2008-04-30 | E-GEOD-10455 | biostudies-arrayexpress

HEK 293T cells RNA-seq data treated with 5-aza-2-deoxycytidine

Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic M-bM-^@M-^\imprintM-bM-^@M-^] of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. mRNA profile of 5 different samples of HEK 293T cells treated with 5-aza-CdR

2015-02-13 | E-GEOD-62591 | biostudies-arrayexpress

MRNA expression data from human breast cancer cell lines after demethylation treatment.

Project description:The contribution of aberrant DNA methylation and the downstream effects in tumorogenesis through silencing of tumor suppressor genes (TSGs) and microRNAs has been investigated. Since these epigenetic alterations can be reversed, we investigated the effects of the epigenetic therapy in breast cancer cell lines. We used microarrays to investigate the global gene expression profile after demethylation treatment with 5-aza-2’-deoxycytidine (DAC) in breast cancer cell lines and identified distinct classes of early and late systematic stable or transient effects of the treatment. Three selected breast cell lines including MDA-MB231 (a highly aggressive cell line), SKBR3 (a non-aggressive cell line) and HB2 (a breast epithelial cell line as control) were subject for RNA isolation before treatment, after treatment with DAC and at five point follow-ups (1st, 3rd, 5th, 7th and 10th passages) at “drug holiday” condition and hybridized on Affymetrix microarrays.

2012-01-24 | E-GEOD-28968 | biostudies-arrayexpress

MicroRNA expression data from human breast cancer cell lines after demethylation treatment.

Project description:The contribution of aberrant DNA methylation and the downstream effects in tumorogenesis through silencing of tumor suppressor genes (TSGs) and microRNAs has been investigated. Since these epigenetic alterations can be reversed, we investigated the effects of the epigenetic therapy in breast cancer cell lines. We used microarrays to investigate the global microRNA expression profile after demethylation treatment with 5-aza-2’-deoxycytidine (DAC) in breast cancer cell lines and identified distinct classes of early and late systematic stable or transient effects of the treatment. Three selected breast cell lines including MDA-MB231, SKBR3, BT549, HS578T, MCF7 and HB2 (a breast epithelial cell line as control) were subject for miRNA isolation before treatment, after treatment with DAC and at five point follow-ups (1st, 3rd, 5th, 7th and 10th passages) at “drug holiday” condition and hybridized on Affymetrix microarrays.

2012-01-24 | E-GEOD-28969 | biostudies-arrayexpress

Genome-wide maps of RNAPII Ser5(P) in HEK 293T cells after treatment with 5-aza-CdR

Project description:DNA methylation can be abnormally regulated in human disease and associated with effects on gene transcription that appear to be causally related to pathogenesis. The potential to use pharmacological agents that reverse this dysregulation is therefore an attractive possibility. To test how 5-aza-2M-bM-^@M-^Y-deoxycytidine (5-aza-CdR) influences the genome therapeutically, we exposed non-malignant cells in culture to the agent and used genome-wide assays to assess the cellular response. We found that cells allowed to recover from 5-aza-CdR treatment only partially recover DNA methylation levels, retaining an epigenetic M-bM-^@M-^\imprintM-bM-^@M-^] of drug exposure. We show very limited transcriptional responses to demethylation of not only protein-coding genes but also loci encoding non-coding RNAs, with a limited proportion of the induced genes acquiring new promoter activation within gene bodies. The data revealed an uncoupling of DNA methylation effects at promoters, with demethylation mostly unaccompanied by transcriptional changes. The limited panel of genes induced by 5-aza-CdR resembles those activated in other human cell types exposed to the drug, and represents loci targeted for Polycomb-mediated silencing in stem cells, suggesting a model for the therapeutic effects of the drug. Our results do not support the hypothesis of DNA methylation having a predominant role to regulate transcriptional noise in the genome, and indicate that DNA methylation acts only as part of a larger complex system of transcriptional regulation. The targeting of 5-aza-CdR effects with its clastogenic consequences to euchromatin raises concerns that the use of 5-aza-CdR has innate tumorigenic consequences, requiring its cautious use in diseases involving epigenetic dysregulation. Examination of RNAPII Ser5(P) localization by ChIP-seq in HEK 293T cell after treatment with 5-aza-CdR.

2015-02-13 | E-GEOD-62695 | biostudies-arrayexpress

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