DNA methylation profiles of IRAK-M gene in untreated or drug-treated human melanoma cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143614 | GEO | 2020/01/15
REPOSITORIES: GEO
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Project description:The impact of drugs inhibiting DNA methylation (5-aza-2'-deoxycytodine, DAC) and EZH2 (EPZ-6438) on the neuroblastoma methylome was analyzed in two neuroblastoma cell lines. Parallel analyses investigated associated changes in histone modification and RNA expression. The neuroblastoma cell lines Be(2)-C and IMR5-75 were treated with a combination of DAC and EPZ-6438. Controls were treated with solvent (DMSO). DNA was isolated, bisulphite converted and hybridised to the llumina HumanMethylation450 BeadChip
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Project description:The impact of drugs inhibiting DNA methylation (5-aza-2'-deoxycytodine, DAC) and EZH2 (EPZ-6438) on H3K27me3 coverage was analyzed in two neuroblastoma cell lines. Parallel analyses investigated associated changes in RNA expression and DNA methylation. The neuroblastoma cell lines Be(2)-C and IMR5-75 were treated with a combination of DAC and EPZ-6438. Controls were treated with solvent (DMSO). H3K27me3 ChIP seq was done to investigate treatment-related changes of this mark. In addition, H3K4me3 and H3K27ac ChIP seq was done in DMSO treated samples to identify putative regulatory regions.
2016-09-08 | E-GEOD-80445 | biostudies-arrayexpress
Project description:Impressive studies have been well documented that Enhancer of zeste homolog 2 (EZH2) could have a role in inflammation as well as a wide range of malignancies; however, the underlying mechanisms remain largely unaddressed. Microglial activation is a key process in the production and release of numerous pro-inflammatory mediators that plays an important role in central nervous system (CNS) inflammation and neurodegeneration. Therefore, our aim was to investigate whether inhibition of EZH2 with selective small molecule inhibitors EPZ-6438 protects against neonatal microglia activation. First, we find that BV-2 microglia, LPS can rapidly increase EZH2 mRNA level and subsequently we performed gene expression profiles and networks in resting, EPZ-6438, LPS and LPS+EPZ-6438 challenged BV-2 microglia by transcriptome RNA sequencing and bioinformatic analyses. By examining RNA sequencing we identified EPZ-6438 target genes and co-regulated modules that were critical in inflammation. We also identified unexpected relationships between the inducible transcription factors (TFs), motif strength, and the transcription of key inflammatory mediators. Furthermore, we showed that EPZ-6438 controls important inflammatory genes targets by modulating interferon regulatory factor (IRF) 1, IRF8, Signal transducer and activator of transcription (STAT) 1 levels at their promoter site. Our unprecedented findings demonstrate that pharmacological interventions built upon EZH2 inhibition by EPZ-6438 could be a useful therapeutic application in neuroinflammatory diseases associated with microglia activation.
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Project description:Mutations within the catalytic domain of the histone methyltransferase (HMT) EZH2 have been identified in subsets of Non-Hodgkin Lymphoma (NHL) patients. These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We previously reported the discovery of a potent, selective, S-adenosyl-methionine-competitive and orally bioavailable small molecule inhibitor of EZH2, EPZ-6438. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent manner in both EZH2 wild type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) led to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of xenograft-bearing mice with EPZ-6438 leads to dose-dependent tumor growth inhibition and eradication of genetically altered NHL with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 day after stopping compound treatment in two EZH2 mutant xenograft models. These data confirm the dependency of mutant NHL on EZH2 activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers. To identify potential biomarker and gain mechanistic insights in EPZ6438 treated lymphoma, lymphoma cell lines with or without EZH2 Y641 mutation were treated with EPZ6438 at Lowest Cytotoxic Concentration (LCC) and 10xLCC. Transcriptomes were profiled on Affemetrix U133 Plus2 chips. Differentially expressed genes and pathways upon compound treatment were anayzed. Lymphoma cell lines WSU-DLCL2, SU-DHL6, Pfeiffer, and Karpas422 were treated by EPZ6438 for 2 days, 4 days and 6 days. Treatment doses are LCC and 10xLCC of each cell lines. KARPAS_422, SUDHL6, and WSU_DLCL2 have the EZH2 Y641 mutation. PFEIFFER does not have the EZH2 Y641 mutation.
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Project description:EZH2 is a H3K27 methylase and a target of cancer epigenetic treatments. We recently reported the oncogenic roles and NTRK1 (TRKA) epigenetic regulation by EZH2 in the MYCN-amplified aggressive neuroblastomas (NB) (L. Here, we investigated the effects and function of small molecule EZH2 inhibitor (EZH2i) on aggressive NB model cell lines. We examined the antitumor effects of EZH2i using WST assay and colony formation assay. By EZH2i treatments, suppression of proliferation, G0/G1 cell cycle arrest, and apoptosis were observed in sensitive NB cells dose-dependently, whereas they were not observed in resistant NB cells. Transcriptome analysis and GSEA indicated significant changes were observed in the gene set related to differentiation and cell cycle arrest in the sensitive cells. We selected genes induced at mRNA level by EZH2i only in the sensitive cells and confirmed tumor suppressor function in NB cells. Almost of the EZH2i-induced gene promoters were marked by H3K27me3 in the sensitive NB cell line. Interestingly, a part of the EZH2i-induced gene promoters have CpG islands and methylated in NB tumor samples registered in databases and the EZH2i-resistant NB cells. Further, combination of EPZ-6438 and 5-aza-deoxycitide, resulted in effective suppression of proliferation in the EPZ-6438-resistant 3 NB cell lines. Transcriptome/methylome analysis of the EPZ-6438 and 5-aza-deoxycitide-treated NB cells revealed the combinational epigenetic regulation of the tumor suppressors and oncogene expression. Finally, we found that methylome analysis of the promoter regions, e.g. VSTM2L, GPNMB, and TIMP3 CpG islands can be biomarkers of EPZ-6438-registancy in unfavorable NB patients. These responsible CpG island methylation appears to be biomarkers for the application of EZH2i/DNMTi combination therapy.
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