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Novel targeting of DNA methyltransferase activity inhibits Ewing sarcoma cell proliferation and enhances tumor cell sensitivity to DNA damaging drugs by activating the DNA damage response

ABSTRACT: Novel targeting of DNA methyltransferase activity inhibits Ewing sarcoma cell proliferation and enhances tumor cell sensitivity to DNA damaging drugs by activating the DNA damage response

PROVIDER: PRJNA834788 | ENA |

REPOSITORIES: ENA

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Novel targeting of DNA methyltransferase activity inhibits Ewing sarcoma cell proliferation and enhances tumor cell sensitivity to DNA damaging drugs by activating the DNA damage response

Project description:Genome wide epigenomic analysis of Ewing Sarcoma human cell lines treated with 5AzadC and MC3343. Samples included 9 x TC-71, 9 x A673 samples, and 8 x PDX samples. For each cell line and condition ( 5AzadC, MC3343, Contol), we created 3 replicates, except PDX with 5AzadC treatment for which only 2 samples were created.

2022-06-01 | GSE202143 | GEO

Chemotherapy With DNA Damaging Agents In Colorectal Cancer

Project description:Chemotherapy Treatment alone with DNA damaging drugs might be as effective as chemotherapy combined with surgery in colorectal cancer (CRC) avoiding surgery complications.

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Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response.

Project description:DNA methylation is an important component of the epigenetic machinery that regulates the malignancy of Ewing sarcoma (EWS), the second most common primary bone tumor in children and adolescents. Coordination of DNA methylation and DNA replication is critical for maintaining epigenetic programming and the DNMT1 enzyme has been demonstrated to have an important role in both maintaining the epigenome and controlling cell cycle. Here, we showed that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 induces a specific depletion of DNMT1 and affects EWS tumor proliferation through a mechanism that is independent on DNA methylation. Depletion of DNMT1 causes perturbation of the cell cycle, with an accumulation of cells in the G1 phase, and DNA damage, as revealed by the induction of γH2AX foci. These effects elicited activation of p53-dependent signaling and apoptosis in p53wt cells, while in p53 mutated cells, persistent micronuclei and increased DNA instability was observed. Treatment with MC3343 potentiates the efficacy of DNA damaging agents such as doxorubicin and PARP-inhibitors (PARPi). This effect correlates with increased DNA damage and synergistic tumor cytotoxicity, supporting the use of the DNMTi MC3343 as an adjuvant agent in treating EWS.

| S-EPMC9197596 | biostudies-literature

PAPERCLIP of cultured cells with/without DNA-damaging treatments

Project description:PAPERCLIP of cultured cells with/without DNA-damaging treatments

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Identifying Novel Predictors of Resistance to DNA Damaging Agents

Project description:We have investigated whether gene expression signatures can be used to predict inter-individual responses to DNA damaging agents We used microarrays to detail inter-individual variation in gene expression across a healthy population under basal and damage induced conditions Keywords: dose (MNNG)

2008-09-23 | GSE10313 | GEO

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma

Project description:Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

2017-01-30 | GSE88826 | GEO

USP1 expression driven by EWS-FLI1 transcription factor stabilizes Survivin and promotes Ewing sarcoma cell survival

Project description:Ewing sarcoma (EWS) is a malignant pediatric bone cancer. Most Ewing sarcomas are driven by EWS-FLI1 oncogenic transcription factor that plays roles in transcriptional regulation, DNA damage response, cell cycle checkpoint control, and alternative splicing. USP1, a deubiquitylase which regulates DNA damage and replication stress responses, is overexpressed at both the mRNA and protein levels in EWS cell lines compared to human mesenchymal stem cells, the EWS cell of origin. The functional significance of high USP1 expression in Ewing sarcoma is not known. Here, we identify USP1 as a transcriptional target of EWS-FLI1 and a key regulator of EWS cell survival. We show that EWS-FLI1 knockdown decreases USP1 mRNA and protein levels. ChIP and ChIP-seq analyses show EWS-FLI1 occupancy on the USP1 promoter. Importantly, USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. We observe destabilization of Survivin (also known as BIRC5 or IAP4) and activation of caspases-3 and -7 following USP1 knockdown or inhibition in the absence of external DNA damage stimuli. Notably, EWS cells display hypersensitivity to combinatorial treatment of doxorubicin or etoposide, EWS standard of care drugs, and USP1 inhibitor compared to single agents alone. Together, our study demonstrates that USP1 is regulated by EWS-FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes EWS cells to standard of care chemotherapy.

2024-01-26 | PXD041033 | Pride

Transcriptome analysis of the extremophile tardigrade Hypsibius exemplaris exposed to the DNA-damaging agent bleomycin

Project description:Transcriptome analysis of the extremophile tardigrade Hypsibius exemplaris exposed to the DNA-damaging agent bleomycin

2024-05-07 | GSE168917 | GEO

DNA-damaging agent and immune inducer synergistically induced defence gene expression in Arabidopsis

Project description:We used microarrays to identify differentially expressed genes after DNA-damaging agent bleomycin (BLM) and/or immune inducer 2, 6-dichloroisonicotinic acid (INA) treatment. We focused on those genes that were synergistically induced by co-treatment (BLM+INA).

2013-11-14 | GSE44793 | GEO

Transcriptomics Analysis of Diploid and Tetraploid Worms Exposed to DNA-Damaging Chemotherapeutics

Project description:To establish the consequences of whole-animal tetraploidy, we generated stable C. elegans worm strains that are tetraploid in every cell in their body and exposed them to DNA damaging chemotherapeutics doxorubicin and cisplatin at doses that do not cause growth delay. Exposures were carried out for 48 h beginning at L1 stage.

2023-08-07 | GSE232747 | GEO

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