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

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

PROVIDER: PRJNA412413 | ENA |

REPOSITORIES: ENA

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

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

| PRJNA412412 | ENA

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

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 | GSE104359 | GEO

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

2019-07-31 | GSE104360 | GEO

SUMO pulldown proteomics Namalwa 5-Aza-2' deoxycytidine treatment

Project description:Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.

2023-03-17 | PXD038620 | Pride

SUMO pulldown, U2OS, proteomics, 4 hour 20 hour 5-Aza-2' deoxycytidine treatment

2023-03-17 | PXD038617 | Pride

MCF7 cells gene expression change by inducing CpG demethylation using 5-Aza-2'-deoxycytidine (Aza)

2011-08-18 | GSE31441 | GEO

5-aza-2-deoxycytidine treatment of Swarm rat chondrosarcoma cells

Project description:The puropose of this experiment was to identify gene expression changes that result from 5-aza-2-deoxycytidine induced DNA demethylation of Swarm rat chondrosarcoma cells. The gene expression profiles of untreated Swarm rat chondrosarcoma cells were compared to the gene expression profiles of Swarm rat chondrosarcoma cells that were treated for 5 passages with a low dose of 5-aza-2-deoxycytidine (0.1uM).

2010-08-06 | GSE17598 | GEO

Expression microarray with 5-aza-2'-deoxycytidine-treated Caco-2 cells

Project description:5-aza-2'-deoxycytidine (DAC) treated and untreated Caco-2 cells were compared using an expression microarray.

2011-12-27 | GSE19660 | GEO

MCF7 cells gene expression change by inducing CpG demethylation using 5-Aza-2'-deoxycytidine (Aza)

Project description:Promoter methylation is able to induce downregulation of gene expression. 5-Aza-2'-deoxycytidine(Aza), methytransferase inhibitor, induce CpG demethylation. Here, 5-Aza-2'-deoxycytidine(Aza) is treated in a human breast cancer cell, MCF7, for detection of gene expression change. To analyze gene expression change by aza, control RNA isolated from MCF-7 was compared with RNA isolated from MCF-7 treated with 5uM and 10uM aza.

2011-08-17 | E-GEOD-31441 | biostudies-arrayexpress

Genome-wide DNA demethylation of TGW (neuroblastoma cell line) after treatment of mock and 5-aza-2'-deoxycytidine (5-aza-dC)

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

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