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Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

ABSTRACT: We proved that histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196440 | GEO | 2022/02/10

REPOSITORIES: GEO

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Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [RNA-Seq]

Project description:We proved that histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.

2022-02-06 | GSE196057 | GEO

Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [ChIP-Seq]

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Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors.

Project description:Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.

| S-EPMC9081147 | biostudies-literature

Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

Project description:Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

| PRJNA803182 | ENA

Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

Project description:Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

| PRJNA804909 | ENA

Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [RNA-Seq]

Project description:Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [RNA-Seq]

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Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [ChIP-Seq]

Project description:Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor [ChIP-Seq]

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Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumor

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

2022-02-06 | GSE196058 | GEO

CUT&RUN profiling of histone H3K27ac and H3K27me3 localization after pharmacological inhibition of EZH2 and BET proteins

Project description:NUT carcinoma (NC), an aggressive carcinoma, is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and when fused to NUT forms very large super-enhancers, termed megadomains. Targeting BRD4-NUT with BET bromodomain inhibitors (BETi) are a promising treatment, but limited as monotherapy. To identify additional dependencies in NC, we performed a genetic rescue screen in NC cells depleted of BRD4-NUT and identified EZH2 as a top correlated hit. Indeed, inhibition of EZH2 using the clinical compound, tazemetostat (taz), potently blocked growth of NC cells, and when combined with BETi was highly synergistic. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on megadomain-associated genes. CDKN2A was identified as the only amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-CAS9 screen. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort.

2023-09-14 | GSE228533 | GEO

Effect of EZH2 and BET bromodomain inhibition, alone and combined, on NUT carcinoma gene expression

Project description:To determine mechanisms of synergy between EZH2 and BRD4-NUT, we treated NUT carcinoma cell lines with EZH2 inhibitor, tazemetostat, and/or BET bromodomain inhibitors (ABBV075 pan-BET inhibitor or ABBV744 BD2-selective inhibitor). We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different NUT carcinoma cell lines at two time points, 6h and 96h.

2023-10-05 | GSE208774 | GEO

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