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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62057 | GEO | 2015/04/13

SECONDARY ACCESSION(S): PRJNA263116

REPOSITORIES: GEO

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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

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

2015-04-13 | GSE62056 | GEO

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. Refer to individual Series

2015-04-13 | E-GEOD-62058 | 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 suppresses the interferon-stimulated gene response in non-Hodgkin Lymphoma [ChIP-seq]

Project description:Pharmacological inhibition of the histone lysine methyltransferase EZH2 has emerged as a therapeutic strategy for the treatment of non-Hodgkin Lymphoma (NHL), in particular for cases with mono-allelic mutations in the EZH2 catalytic domain. Potent, selective EZH2 small molecule inhibitors have achieved tumor regression in mutant EZH2-containing preclinical lymphoma models and several of these inhibitors are currently engaged in cancer-focused clinical trials. Here, we show that the presence of EZH2 mutations do not always confer EZH2 inhibitor sensitivity. We discovered that EZH2 is usurped by lymphoma cells to attenuate JAK/STAT signaling and to repress pro-apoptotic interferon response genes. EZH2 inhibition results in the broad induction of interferon-stimulated genes (ISGs) in several phenotypically sensitive NHL cell models. In mutant EZH2-containing insensitive models, EZH2 inhibitors synergize specifically with type I interferons (IFNs) in vitro and in vivo to induce ISGs and apoptosis. The profound combinatorial activity of EZH2 inhibitors and type I IFNs is not restricted to NHL models with mutant EZH2 and, is preferentially observed in models that are not affected by either single agent. Molecular consequences of EZH2 inhibitor and type I IFN combinatorial treatment include STAT1 activation, binding of STAT transcription factor complexes to ISGs, reduction of H3K27me3 levels and increase of H3K4me3 levels at ISG transcriptional start sites, and ISG transcriptional activation. The molecular and anti-proliferative effects of the combination can be suppressed by inactivation of the JAK/STAT signaling pathway, by using the JAK inhibitor ruxolitinib. We suggest that EZH2 inhibitors can be therapeutically combined with type I IFNs for the treatment of NHL.

2023-01-06 | GSE70702 | GEO

EZH2 suppresses the interferon-stimulated gene response in non-Hodgkin Lymphoma [RNA-seq]

2023-01-06 | GSE70622 | GEO

MELK mediates the stability of EZH2 throught site-specific phosphorylation in extranodal natural killer/T-cell lymphoma

Project description:Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry (MS) analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. Interestingly, FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme which deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to Bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor Bortezomib response.

2019-08-26 | PXD015008 | Pride

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

Lysine methylome features in EZH2 wild-type and mutant lymphoma cell line

Project description:We used EZH2i-targeted hematological malignancies as an examples and focused on molecular characterization of EZH2 Y641 mutant hematological cell lines. We used the proteomic strategies and compared the protein expression level and lysine methylation level (including mono-, di-, and trimethylaiton) in EZH2 wild-type (EZH2 WT), EZH2 Y641N and Y641F (EZH2 MUT) cell lines.

2019-12-17 | PXD016779 |

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