Expression data from decitabine-treated and non-treated BR5FVB1-Akt cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE69454 | GEO | 2015/06/03
SECONDARY ACCESSION(S): PRJNA285587
REPOSITORIES: GEO
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Project description:Treatment of cancer cells with anti-cancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumor’s gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anti-cancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited anti-tumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug.
2016-07-18 | PXD003790 | Pride
Project description:Treatment of cancer cells with anti-cancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumor’s gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anti-cancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited anti-tumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug.
2017-03-31 | MSV000080843 | MassIVE
Project description:Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBCs) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype-specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naive breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in TNBC patients treated with decitabine as a second line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene-specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis (GSEA) of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways in decitabine treated cells. Induced genes included those characterized by the viral mimicry response; however knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients. We used microarrays to determine genome-wide expression changes induced by DNA de-methylating agent decitabine in breast cancer cell lines
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Project description:It is well established that low-dose Decitabine treatment can sustain long-term antitumor effects by targeting DNA methylation and altering gene expression32. We performed methylated DNA immunoprecipitation (MEDIP) followed by next-generation sequencing in 5637 cells. Daily Decitabine treatment with 100 nM for 72 hr (with or without 100ng/ml cisplatin treatment) reduced the methylation level at CpG-islands in the genome of 5637 cells . However, this low-dose DEC treatment did not cause a significant reduction of DNA methylation in non-CpG islands regions.Our study represents the first detailed analysis of DNA methylome generated by RNA-seq technology in bladder cancer cells treated with low-dose decitabine. This study help to reveal the direct target genes of decitabine in bladder cancer treatement.
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Project description:Background: Epigenetic modifications such as methylation silencing of genes with CpG-island-associated promoters is frequently observed in cancer. Studies regarding the implications of epigenetic modifications in osteosarcoma (OS) have been limited. The epigenetic drug decitabine is a potential re-activator of silenced genes through de-methylation, and is currently undergoing clinical trials for cancer treatment. No study to date has utilized decitabine to modify gene expression in OS-derived cells to identify gene-specific methylation targets that may have therapeutic importance. The objective of this study was to measure the response of the OS cell line, U-2OS, to decitabine treatment both in vitro and in vivo. Results: Genome-wide screening was used to distinguish decitabine-dependent changes in gene expression in U-2OS and to identify responsive loci with de-methylated CpG regions. U-2OS xenografts were established in the sub-renal capsule of immune-deficient mice to study the effect of decitabine in vivo on tumor growth and differentiation. Genome-wide screening of U-2OS cells in vitro revealed that decitabine treatment at low-dosage (1 µM) caused a significant induction (p<0.0025) in the expression of 88 genes, 13 had a â?¥2-fold change, 11 of which had CpG-island-associated promoters. Interestingly, 6 of these 11 were pro-apoptotic genes. 1 µM decitabine resulted in a significant induction of cell death in U-2OS cells in vitro (p<0.05). Decitabine treatment also reduced tumor volume size significantly (p<0.05) in U-2OS in vivo at a 2.5 mg/kg dose. Histological analysis of U-2OS xenograft sections revealed a lower mitotic activity (p<0.0001), a higher bone matrix production (p<0.0001), and higher apoptosis (p = 0.0329) after treatment. The 6 pro-apoptotic genes were also induced to â?¥2-fold in vivo. Quantitative Methylation Pyrosequencing (Pyro Q-CpG) showed that 4 pro-apoptotic genes had CpG-island DNA de-methylation as a result of treatment in vitro and in vivo. Conclusion: Our data provide new insights regarding the use of epigenetic modifiers in OS, and have important implications for therapeutic trials involving demethylation drugs. The findings of this study suggest an epigenetic mechanism, whereby OS tumor cells silence expression of pro-apoptotic genes through promoter-CpG methylation, to maintain high proliferation capacity and continuous growth. Experiment Overall Design: Total RNA was extracted using the RNeasy kit (Qiagen, Germany) from duplicate experiments of U-2OS cells at Day3 after treatment with 1 µM decitabine or medium alone (control). In each experiment RNA yields were pooled from two independent cultures per treatment arm to minimize experimental noise. For each case, 10 µg of RNA was labeled and hybridized to the Affymetrix HG-U133A GeneChips using the manufacturerâ??s protocol (Affymetrix, Santa Clara, CA) by the Center of Applied Genomics at the Hospital for Sick Children (Toronto, Canada). Data were extracted using the Microarray Suite (MAS) version 5.0 (Affymetrix) and linearly scaled to achieve an average intensity of 150 across each chip. The candidate gene list obtained from the MAS 5.0-extracted data was selected by eliminating genes that were not present in at least one experiment. The arrays were subjected to a pair wise comparison using MAS 5.0, with signal intensities from the no-treatment cells as the baseline. The statistical significance for the change of expression for each probe set between the decitabine treated and control was calculated by the MAS5.0 software. The criteria for gene selection for real-time expression validation analysis was based on the statistically significant up-regulation (p<0.0025) and fold change of â?¥ 2 for expression after decitabine treatment. The gene list was annotated based on the NetAffx data-base (http://www.affymetrix.com/analysis /index.affx) and further verified using the Human Genome Browser data base (http://genome.ucsc.edu/)
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Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples. We cultured 18 different primary AML samples for 7 days, the last 3 days of which included 100 nM decitabine (DAC) or 100 nm cytarabine (AraC). We hypothesized that decitabine treatment would result in detectable and consistent gene expression changes. For comparison, we also analyzed mRNA from cells treated with DMSO control (mock) and mRNA from uncultured cells taken at the time of diagnosis.
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Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples.
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