Zebularine effect on mouse embryonic stem cells manifested as cardiod-myogenic potential: testable hypothesis generation using microarray data
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29072 | GEO | 2011/05/05
SECONDARY ACCESSION(S): PRJNA140283
REPOSITORIES: GEO
Similar Datasets
Project description:Lineage commitment during Embryonic Stem Cells (ESCs) differentiation is controlled not only by a gamut of transcription factors but also by epigenetic events, mainly histone deacetylation and promoter DNA methylation. Moreover, the DNA demethylation agent 5′-Aza-2′-deoxycytidine (AzadC) has been widely described in the literature as an effective chemical stimulus used to promote cardiomyogenic differentiation in various stem cell types; however, its toxicity and instability complicate its use. Thus, the purpose of this study was to examine the effects of zebularine, a stable and non-toxic DNA cytosine methylation inhibitor, on ESCs differentiation. Herein are the Affymetrix Expression data obtained from RNA of murine ESCs treated with zebularine. 9 control samples (replicates) and 9 zebularine samples (replicates).
2011-05-05 | E-GEOD-29072 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms “hemophilic cell adhesion”, “regulation of transcription, DNAdependent” and “Wnt signaling pathway” were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased β-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation-independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer.
2015-03-24 | GSE60446 | GEO
Project description:Transcriptomic changes in human liver cancer cell lines caused by the demethylating drug zebularine. Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in mice. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome.
2011-07-31 | GSE23991 | GEO
Project description:Hepatocellular carcinoma is one of the most common cancers in world wide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine [1-(β-ᴅ-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. Here, we demonstrated that zebularine exhibited antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis. Zebularine treatment down-regulated CDK2 and phosphorylation of retinoblastoma protein (RB), and up-regulated p21WAF/CIP1 and p53. We also found that zebularine treatment up-regulated phosphorylation of p44/42 MAPK. These results suggest that p44/42 MAPK pathway play a role in zebularine induced cell cycle arrest by regulating activity of p21WAF/CIP1 and Rb. Furthermore, we found that zebularine induced apoptosis. Although proapoptotic protein Bax levels were not affected, antiapoptotic protein Bcl-2 level was down-regulated with zebularine treatment. The data in the present study suggest that the action of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results provide a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma.
2013-12-01 | GSE42490 | GEO
Project description:Zebularine is a non-methylable cytidine analog that is used in epigenetic and cancer research. Its application has been shown to activate several transcriptionally silenced genetic elements; however, extent of this activation and other effects on the transcriptome are unknown. Here, we show that zebularine treatment induces preferentially genes associated with DNA damage repair response and this activation is strongly ATR-dependent. The set of up- and down-regulated genes after 24 h zebularine treatment is almost fully contained in the set of genes with changed transcription in response to 24 h MMC treatment. We identified only few genes that were up-regulated in common by longer (5 days) zebularine treatment and loss of epigenetic control in ddm1 mutant. Our results suggest that zebularine does not induce global activation of targets of transcriptional gene silencing and indicate previously unanticipated DNA damaging effects associated with zebularine-treatment.
2014-11-18 | GSE63355 | GEO
Project description:Cultures of DU-145 cells and of LNCaP cells were treated for 216 hours with 100µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use.
2013-10-24 | GSE51629 | GEO
Project description:Transcriptomic changes in human liver cancer cell lines caused by the demethylating drug zebularine. Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine signature that classified liver cancer cell lines into two major subtypes with different drug-responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving liver cancer growth in vitro and in mice. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells leading to increased survival and decreased pulmonary metastasis. Integration of zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome. Each cell line was mock treated or treated with 100uM and 200uM zebularine for 7 days, respectively *** This Series represents the gene expression component of the study.
2011-07-30 | E-GEOD-23991 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma is one of the most common cancers in world wide. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine [1-(β-ᴅ-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on hepatocellular carcinoma cell line HepG2. Here, we demonstrated that zebularine exhibited antitumor activity on HepG2 cells by inhibiting cell proliferation and inducing apoptosis. Zebularine treatment down-regulated CDK2 and phosphorylation of retinoblastoma protein (RB), and up-regulated p21WAF/CIP1 and p53. We also found that zebularine treatment up-regulated phosphorylation of p44/42 MAPK. These results suggest that p44/42 MAPK pathway play a role in zebularine induced cell cycle arrest by regulating activity of p21WAF/CIP1 and Rb. Furthermore, we found that zebularine induced apoptosis. Although proapoptotic protein Bax levels were not affected, antiapoptotic protein Bcl-2 level was down-regulated with zebularine treatment. The data in the present study suggest that the action of the double-stranded RNA-dependent protein kinase (PKR) is involved in inducing apoptosis with zebularine. These results provide a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma. Three each independent batches of zebuluarine-treated and control HepG2 cells were subjected to illumina Human methylation 450K Beadchip analysis.
2013-12-01 | E-GEOD-42490 | biostudies-arrayexpress
Project description:Cultures of DU-145 cells and of LNCaP cells were treated for 216 hours with 100µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use. Total RNA of untreated and treated (100µM zebularine) DU-145 cells (experiment HK_21_DU_145-HK_26_DU_145), and of untreated and treated (100µM zebularine) LNCaP cells (experiment HK_27_LNCaP-HK_32_LNCaP), were subjected to Affymetrix array analysis to detail the overall expression changes after treatment with a DNMT inhibitor. Treated cells showed no obvious signs of zebularine-induced cytotoxicity as revealed by XTT assays.
2013-10-24 | E-GEOD-51629 | biostudies-arrayexpress
Project description:Cultures of A-498 cells were treated for 120hours with 1000µM zebularine (SIGMA) in three independent biological experiments. Zebularine acts as a DNA methyltransferase (DNMT) inhibitor thereby upregulating genes that are inactivated by e.g. promotor hypermethylation. The experiment aimed to search for upregulated transcripts to provide new targets for biomarker development and therapeutic use. 308 candidates were upregulated more than 1.5-fold. Members of the metallothionein group (MT1G, MT1H, and MT2A) were validated in 49 clinical samples of renal cell carcinomas.
2013-10-24 | GSE51627 | GEO