Expression profiling of DNMT1 inhibitors in HCT116 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30985 | GEO | 2011/12/01
SECONDARY ACCESSION(S): PRJNA146197
REPOSITORIES: GEO
Similar Datasets
Project description:Epigenetic changes accompany tumorigenesis and are required for tumor maintenance. Modulation of DNA methylation state, histone acetylation, and histone methylation, as well as reversal of disease-associated epigenetic state aberrations, can be disruptive to malignant disease progression. We produced lipophilic prodrugs of decitabine, which is a DNA methyltransferase inhibitor and is efficacious in treatment of myelodysplastic syndromes when dosed subcutaneously. Comparison of parent and prodrug activities in vitro and in vivo revealed comparable effects and unveiled several novel features of nucleoside analog molecular activity in vitro. HCT116 were treated for 72 hour with Decitabine, Azacytidine and various prodrugs in duplicates at different dose concentrations. Cells were also treated with DMSO as control (quadrpulets), RNA was extracted and samples were hybridized to Affymetrix Hu133plus 2.0 arrays.
2011-12-01 | E-GEOD-30985 | biostudies-arrayexpress
Project description:Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. A reverse proteomic approach has identified the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.
2017-11-13 | PXD007765 | Pride
Project description:The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.
2020-07-28 | GSE152804 | GEO
Project description:DNA methylation and the Polycomb Repression System are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear. By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and PRC2 from Polycomb-target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression. An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining PRC2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease. Three replicates of each sample are compared
2013-02-12 | E-GEOD-44277 | biostudies-arrayexpress
Project description:The epigenetic regulation, for example, DNA methylation, controls the development and differentiation of both tumor cells and immunocytes. Treatment with DNA demethylating agent (such as decitabine) has shown a dramatic clinical benefit in hematological malignancies and solid tumors. However, the influence of epigenetic therapy on host immune system remains unclear. To investigate the effects of low-dose decitabine therapy on T cells, We collected whole blood samples from two solid tumor patients pre and post low-dose decitabine therapy, and detected the expression profiles of PBMCs.
2016-06-30 | E-GEOD-72686 | biostudies-arrayexpress
Project description:Recently, various groups managed to isolate naïve human embryonic stem cell (hESC) state in vitro has come into acceptance. However, a thorough epigenetic characterization of this human ground state, defined as a state without any epigenetic restrictions, and how that compares to mouse is currently lacking. Also, the epigenomic remodeling required to obtain the ground state, and the important transient processes occurring during the remodeling, have remained elusive in human. Here, we address these issues by using an untargeted mass spectrometry-based (MS) approach to profile the histone epigenome in a time-resolved experimental design. Special care was given to defining the naïve hESC state that was reached over 12 passages (P12, 37 days) in feeder-free conditions in this study. We found that conversion is a multi-staged process with a prominent cellular disturbance after stimulation (P3), an increase in cell proliferation between P3 and P6 and a naïve cell state stabilizing between P9 and P12. In total, 20 different histone post-translational modifications (hPTMs) changed significantly over time from primed to naïve hESCs. Most notably, H3K27me3 is the most prominently increasing hPTM in naïve hESCs, in line with what we recently described in mouse. Essentially, we present a first roadmap of the changing human histone epigenome from primed to naïve state and emphasize that the overlap with mouse hints at a conserved Mammalian epigenetic signature of the ground state.
2019-11-27 | PXD013067 | Pride
Project description:Decitabine and Azacytidine are considered as epigenetic drugs that induce DNA-methyltransferase (DNMT)-DNA crosslinks, resulting in DNA-hypomethylation and -damage. Although they are already applied against myeloid cancers, important aspects of their mode of action remain unknown, highly limiting their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA-damage. Under low DNMT-activity, only Decitabine has a substantial impact. Conversely, when DNMT-activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA-hypomethylation or RNA-associated processes. By investigating proteome dynamics on chromatin, we show that Decitabine induces a strictly DNMT-dependent multifaceted DNA-damage response based on chromatin-recruitment, but not expression level changes of repair-associated proteins. The choice of DNA-repair pathway herby depends on the severity of Decitabine-induced DNA-lesions. While under moderate DNMT-activity, mismatch (MMR), base-excision (BER) and Fanconi anemia-dependent DNA-repair combined with homologous recombination are activated in response to Decitabine, high DNMT-activity and therefore immense replication stress, induce activation of MMR and BER followed by non-homologous end-joining.
2024-06-19 | PXD045353 | Pride
Project description:Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated bythe de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitors (DNMTi) and/or Histone deacetylase transferase inhibitors (HDACi), to assemble a de novo transcriptome and identified 3,023 ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs), encoding for 61,426 open reading frames. Using Immunopeptidomics, we further demonstrate the human leukocyte antigen (HLA) presentation of treatment-induced neoepitopes (t-neoepitopes) derived from TINPATs. We illustrate the potential of the identified t-neoepitopes to elicit a T-cell response and cancer cell killing. The presence of t-neoepitopes was further verified in AML patient samples 48/96 h after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight a novel mechanism of ERV-derived neoantigens in epigenetic and immune therapies.
2023-08-18 | PXD035750 | Pride
Project description:Analyses of mirna transcript levels following exposure to the drug triptolide in vitro and prodrug minnelide in xenograft pancreatic tumor mouse models. Response of pancreatic adenocarcinoma cell lines to minelide in vitro and exposure to its prodrug triptolide in SCID mouse tumors derived from the same cell lines.
2013-11-12 | E-GEOD-46188 | biostudies-arrayexpress
Project description:DNA methylation and the Polycomb Repression System are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear. By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and PRC2 from Polycomb-target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression. An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining PRC2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.
2013-02-12 | GSE44277 | GEO