Genome-wide DNA demethylation of HML58-3 (a derivative cell line of HCT116) after treatment of DAC, OR-2003, and OR-2100
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE134293 | GEO | 2019/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:A derivative cell line of HCT116, HML58-3, was established to detect DNA demethylating agents [Okochi-Takada E, Epigenetics. 2018;13:147-55.]. HML58-3 cells were treated with DNA demethylating agents (decitabine, OR-2003, and OR-2100) or mock. A genome-wide gene expression analysis was performed using SurePrint G3 Human Gene Expression 8 x 60K v2 Microarray.
2019-08-01 | GSE134294 | GEO
Project description:To evaluate the impact of DNA demethylating agents on our mouse MDS model, we chose 5-aza-2’-deoxycytidine, decitabine (DAC), one of the DNA demethylating agents, which is incorporated into DNA but not RNA and has 10-fold more potency in DNA demethylation than 5-azacitidine. We transplanted Tet2KD/KDEzh2Δ/Δ MDS cells into lethally irradiated secondary recipients and treated them with DAC (low dose DAC at 0.25mg/kg, 3 times a week, intraperitoneal injection), then purified LSK HSPCs and evaluated the expression profiles.
2017-03-15 | GSE79204 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of malignant epithelial cells from a KPC-Brca1 mouse pancreatic carcinoma, with 0.5 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.
2013-01-01 | E-GEOD-42365 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of cancer-associated fibroblasts (CAFs) from a KPC-Brca1 mouse pancreatic carcinoma, with 2 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.
2013-01-01 | E-GEOD-42364 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
2013-01-01 | GSE42365 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
2013-01-01 | GSE42364 | GEO
Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.
2012-03-21 | E-GEOD-20945 | biostudies-arrayexpress
Project description:A neuroblasoma cell line, TGW, was treated with a DNA demethylating agents (5-aza-2'-deoxycytidine: 5-aza-dC). Genome-wide DNA methylation was analyzed using the Infinium Human MethylationEPIC BeadChip.
2021-07-23 | GSE180660 | GEO
Project description:Epigenetic reprogramming using demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a high therapeutic efficacy, despite its small demethylating effect. Here, we aimed to reveal the mechanisms of how such low-dose treatment shows high efficacy by focusing on epigenetic reprograming at the single-cell level. Single-cell RNA-sequencing of HCT116 cells treated with decitabine (DAC) revealed that up-regulated genes were highly variable at the single-cell level. To analyze functional consequences at the single-cell level, DAC-treated HCT116 cells were cloned. While only partial reduction of methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes was observed, depending upon clones. For example, p16 was completely demethylated in the H3-32 clone out of 9 clones, and this clone showed slower proliferation than other clones without demethylation. In addition, in this clone, the fraction of cells with tetraploid became much larger, indicating that cellular senescence was induced. These results showed that epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the high efficacy of low-dose DNA demethylating therapy.
2021-04-10 | GSE171429 | GEO
Project description:Treatment with demethylating agents in combination with tyrosine kinase inhibitors have shown improved molecular responses and survival benefits in patients with TKI-resistant or advanced-phase CML. However, little is known regarding underlying mechanism of the combination anti-tumor effect of demethylating agents and tyrosine kinase inhibitors. To analyze the combination effect, we have compared gene expression profiles among chronic myeloid leukemia (CML) cell lines (K562, KBM5) treated with imatinib (IM), a new demethylating agent, OR-2100 (OR21), and these combination therapy.
2020-09-09 | GSE157620 | GEO