Effect of EZH2 and BET bromodomain inhibition, alone and combined, on NUT carcinoma gene expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA860981 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20351933_1.fastq.gz | Fastqsanger.gz | |||
| SRR20351933_2.fastq.gz | Fastqsanger.gz | |||
| SRR20351934_1.fastq.gz | Fastqsanger.gz | |||
| SRR20351934_2.fastq.gz | Fastqsanger.gz | |||
| SRR20351935_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET selective bromodomain inhibitors have demonstrated on-target activity in NMC patients, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or 'standard' chemotherapy.
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Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) alone and in combination for 72 hours
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Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) or BAZ siRNA alone and in combination with JQ1 for 48 hours
2019-07-09 | GSE116879 | GEO
Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 µM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).
2013-02-25 | E-GEOD-43392 | biostudies-arrayexpress
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
Project description:IL-17-producing T helper (TH17) cells have been selected through evolution for their ability to control fungal and bacterial infections. It is also firmly established that their aberrant generation and activation results in autoimmune conditions. Using a characterized potent and selective small molecule inhibitor, we show that the bromodomain and extra-terminal domain (BET) family of chromatin adaptors plays fundamental and selective roles in human and murine TH17 differentiation from naM-CM-/ve CD4+ T cells, as well as in the activation of previously differentiated TH17 cells. We provide evidence that BET controls TH17 differentiation in a bromodomain-dependent manner through a mechanism that includes the direct regulation of multiple effector TH17-associated cytokines, including IL17, IL21 and GMCSF. We also demonstrate that BET family members Brd2 and Brd4 associate with the Il17 locus in TH17 cells, and that this association requires bromodomains. We recapitulate the critical role of BET bromodomains in TH17 differentiation in vivo and show that therapeutic dosing of the BET inhibitor is efficacious in mouse models of autoimmunity. Our results identify the BET family of proteins as a fundamental link between chromatin signaling and TH17 biology, and support the notion of BET inhibition as a point of therapeutic intervention in autoimmune conditions. 4 samples were analyzed: two conditions in duplicate. Naive T cells were placed in conditions leading to TH17 differentiation, with and without BET inhibitor. RNA was collected at 48 hours.
2013-09-20 | E-GEOD-37270 | biostudies-arrayexpress
Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma.
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Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function was unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Nut’s major function is therefore to use the ubiquitous HATs p300/CBP to direct a cell-type specific histone hyperacetylation. Its ectopic activity in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain binding loop that normally operates in post-meiotic spermatogenic cells.
2018-10-02 | PXD008727 | Pride