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EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Barbara Bryant

PROVIDER: E-GEOD-62058 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation.

Bradley William D WD Arora Shilpi S Busby Jennifer J Balasubramanian Srividya S Gehling Victor S VS Nasveschuk Christopher G CG Vaswani Rishi G RG Yuan Chih-Chi CC Hatton Charlie C Zhao Feng F Williamson Kaylyn E KE Iyer Priyadarshini P Méndez Jacqui J Campbell Robert R Cantone Nico N Garapaty-Rao Shivani S Audia James E JE Cook Andrew S AS Dakin Les A LA Albrecht Brian K BK Harmange Jean-Christophe JC Daniels Danette L DL Cummings Richard T RT Bryant Barbara M BM Normant Emmanuel E Trojer Patrick P

Chemistry & biology 20141101 11

The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of hi ...[more]

PMID: 25457180

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EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation [RNA-Seq]

Project description:Here we report the discovery of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, their application across a large lymphoma cell panel and their efficacy in GCBDLBCL xenograft models. RNA-seq of KARPAS-422 cell line RNA, in duplicate, treated with DMSO as control, and EZH2 inhibitors CPI360, EPZ-6438 and GSK126. Eight samples in total.

2015-04-13 | E-GEOD-62056 | biostudies-arrayexpress

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation [ChIP-Seq]

Project description:Here we report the discovery of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, their application across a large lymphoma cell panel and their efficacy in GCBDLBCL xenograft models. Baseline ChIP-seq measurement of KARPAS-422 cell line H3K27me3 levels, without treatment. Two samples -- H3K27me3 and Input included as control.

2015-04-13 | E-GEOD-62057 | biostudies-arrayexpress

DNA methylation analysis of neuroblastoma cell lines treated with epigenetic drugs

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

2016-09-08 | E-GEOD-80243 | biostudies-arrayexpress

ChIP-seq-based analysis of differential K27me3 coverage in neuroblastoma cell lines treated with epigenetic drugs

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

Proteomic profiling reveals distinct phases to the restoration of chromatin following DNA replication

Project description:Chromatin organization must be maintained during cell proliferation to preserve cellular identity and genome integrity. However, DNA replication results in transient displacement of DNA bound proteins, and it is unclear how they regain access to newly replicated DNA. Using quantitative MS-based proteomics coupled to Nascent Chromatin Capture, we provide time resolved binding kinetics for thousands of proteins behind replisomes of mid-S replicated regions. This shows that most proteins regain access within the first 15 minutes after the passage of the fork. In contrast, 25% of the identified proteins do not, and this delay cannot be inferred from their known function, physicochemical properties, or nuclear abundance. Here, we provide data where we impaired the H3K27me3 restoration to analyse its impact into chromatin restoration. To this aim, we used the EPZ-6438 inhibitor, which blocks the histone methyltransferase EZH2. Two time-points are analysed by NCC along the cell cycle in late replicated regions: nascent chromatin, just after the passage of the fork, and a sample 16 hours later, in late G1 phase. Our data support that H3K27me3 have an important role in chromatin restoration. Data available in this entry are related with the supplementary table 6 from our manuscript.

2023-02-02 | PXD038376 | Pride

Gene expression profiling of two DLBCL cell lines upon shRNA mediated knockdown of EZH2

Project description:We studied transcriptional changes by Affymetrix human microarrays in 2 DLBCL cell lines as a result of shRNA mediated knockdown of EZH2. In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. Pfeiffer and KARPAS-422 cells were treated with either shRNA targeting EZH2 (shEZH2) or a non targeting control (shNTC) for 10 days.

2012-10-12 | E-GEOD-41239 | biostudies-arrayexpress

Alternative mRNA splicing controls functions of the human H3K27 demethylase UTX/KDM6A

Project description:The UTX/KDM6A gene encodes the UTX histone H3K27 demethylase, which plays an important role in mammalian development and is frequently mutated in cancers and particularly, in urothelial cancers. Using BioID technique, we explored the interactome of different UTX isoforms.

2024-01-28 | PXD041254 | Pride

RNA expression analysis of neuroblastoma cell lines treated with epigenetic drugs

Project description:The impact of drugs inhibiting DNA methylation (5-aza-2'-deoxycytodine, DAC) and EZH2 (EPZ-6438) on the neuroblastoma transcriptome was analyzed in two neuroblastoma cell lines. Parallel analyses investigated associated changes in histone modification and DNA methylation. The neuroblastoma cell lines Be(2)-C and IMR5-75 were treated with DAC and EPZ-6438 in combination or alone. Controls were treated with solvent (DMSO). RNA was isolated and sequenced.

2016-09-08 | E-GEOD-79859 | biostudies-arrayexpress

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-04-13 | GSE62058 | GEO

EZH2 inhibitor efficacy in non-Hodgkin lymphoma does not require suppression of H3K27 mono-methylation [ChIP-Seq]

2015-04-13 | GSE62057 | GEO