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EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [RNA-seq]

ABSTRACT: EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [RNA-seq]

PROVIDER: PRJNA862711 | ENA |

REPOSITORIES: ENA

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EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation.

Project description:EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation.

| PRJNA862706 | ENA

EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [ChIP-seq]

Project description:EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [ChIP-seq]

| PRJNA862710 | ENA

EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [ChIP-seq]

Project description:The long-term survival of advanced urothelial carcinoma (UCa) patients is limited due to an innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa, and therefore, hypothesized that EPZ-011989, a small molecule catalytic inhibitor of EZH2, might have anti-tumor effects in UCa. Here we show that in a carcinogen-induced mouse bladder cancer model, EZH2 inhibition results in reduced tumor progression, elevated tumor infiltrating T cells, increased pro-inflammatory cytokine secretion and MHC class II expression on UCa cells. Treatment of mice with EPZ011989 causes increased MHC class II expression on the urothelium, and was able to activate CD4+ T cells, which is completely abrogated with genetic ablation of the acquired immune system. These findings support a unique role for EZH2 catalytic activity in mediating UCa immune evasion and, for the first time, prove the efficacy of EZH2 catalytic inhibitors in a UCa model, a finding that can potentially be expanded to humans with UCa.

2022-08-15 | GSE209852 | GEO

EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [RNA-seq]

2022-08-15 | GSE209851 | GEO

EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation.

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

2022-08-15 | GSE209853 | GEO

Transcriptome analysis for KDM6A mutated urothelial bladder carcinoma and EZH2 inhibitor treated KDM6A mutated urothelial bladder carcinoma

Project description:Purpose: The goals of this study are to compare 1. The transcription profile in KDM6A wildtype and KDM6A mutated urothelial bladder carcinoma. 2. The transcriptional changes in KDM6A mutated urothelial bladder carcinoma upon EZH2 inhibitor treatment.

2017-03-01 | GSE92723 | GEO

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

EZH2 Mediated Metabolic Rewiring Promotes High-grade Serous Ovarian Cancer Progression Independently of Histone Methyltransferase Activity II

Project description:Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and exerts an oncogenic role in various cancers through catalytic-dependent or -independent pathways. However, the mechanisms contributing to high-grade serous ovarian cancer (HGSOC) are not well understood. Here, we showed that a subgroup of HGSOC patients with high EZH2 expression but low H3K27me3 level exhibited the worst prognosis. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked ovarian cancer cell proliferation and tumorigenicity in vitro and in vivo. We further demonstrated that EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing the tricarboxylic acid cycle (TCA cycle), which contributed to the progression of HGSOC. Together, these data reveal a novel oncogenic role of EZH2 in HGSOC, and provide potential therapeutic strategies in HGSOC by targeting EZH2 non-catalytic activity.

2023-08-11 | GSE211307 | GEO

EZH2 Mediated Metabolic Rewiring Promotes High-grade Serous Ovarian Cancer Progression Independently of Histone Methyltransferase Activity

Project description:Despite EZH2 is overexpressed and exerts an oncogenic role in various cancer through catalytic-dependent or -independent manner, the mechanisms of EZH2 contributing to high-grade serous ovarian cancer (HGSOC) are incompletely understood. Here, we showed that a subgroup of HGSOC patients with high EZH2 expression but low H3K27me3 level exhibited worst prognosis. We demonstrated that EZH2 degradation but not catalytic inhibition profoundly lowered EZH2 protein and blocked cell proliferation and tumorigenicity in vitro and in vivo. Ectopic expression of EZH2 without SET domain (EZH2-∆SET), which is known to be essential for catalytic activity, restored the phenotypes of EZH2 degradation. Mechanistically, we identified that IDH2 was transactivated by EZH2 to impair metabolic rewiring by disrupting the TCA cycle, which contributed to the oncogenic role of EZH2 in OC. Together, these data reveal a novel carcinogenic role of EZH2 in HGSOC, and provide potential strategies in HGSOC by targeting EZH2 non-catalytic activity.

2023-08-11 | GSE185604 | GEO

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells [RNA-seq]

Project description:The SWI/SNF chromatin remodeling complex is altered in ~20% of human cancers. ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated epigenetic regulator in human cancers. Inactivation of the SWI/SNF complex is synthetically lethal with inhibition of EZH2 activity. EZH2 inhibitors are entering clinical trials for specific tumor types with SWI/SNF mutations. However, mechanisms of de novo or acquired resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.

2019-02-10 | GSE110449 | GEO

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