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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208774 | GEO | 2023/10/05

REPOSITORIES: GEO

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Combined targeting of the BRD4-NUT-p300 axis in NUT midline carcinoma by dual selective bromodomain inhibitor, NEO2734

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.

2020-06-19 | GSE142481 | 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 inhibition on NUT carcinoma gene expression over time

Project description:To determine roughly the time point at which most transcriptional changes occur in response to tazemetostat (taz, aka EPZ-6438 (EPZ)) treatment of NUT carcinoma cells, we performed RNAseq over a time course.

2023-09-20 | GSE232838 | GEO

NUT Carcinoma

Project description:NUT Carcinoma

| PRJNA744550 | ENA

Differentiation of NUT midline carcinoma by epigenomic reprogramming

Project description:Knockdown of the oncogene, BRD4-NUT, in a rare cancer, termed NUTmidline carcinoma (NMC), results in morphologic features consistent with squamous differentiation. Treatment with the HDAC-inhibitor, TSA, appears to cause the same phenotype. Here, we use gene expression profiling to compare the changes in gene expression following BRD4-NUT knockdown and TSA treatment. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following siRNA knockdown versus control in duplicate. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following treatment with TSA versus etoh control in triplicate

2011-07-01 | E-GEOD-18668 | biostudies-arrayexpress

Differentiation of NUT midline carcinoma by epigenomic reprogramming

2011-07-01 | GSE18668 | GEO

A genetically engineered mouse model (GEMM) of NUT carcinoma (RNA-Seq)

Project description:NUT carcinoma (NC) is a highly aggressive subtype of squamous carcinoma driven by the BRD4-NUT fusion oncoprotein. Closely resembling human NC (hNC), GEMM tumors (mNC) are poorly differentiated squamous carcinomas that express high levels of MYC and metastasize to organs (liver, lung) and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes, characterized by RNAseq and CUT&RUN, show striking overlap with those of primary GEMM tumors. As in hNC, BRD4-NUT functions to block differentiation and maintain growth of mNC, as evidenced by BRD4-NUT knockdown and treatment of mNC cell lines with BET bromodomain inhibitors (BETi). Mechanistically, GEMM primary tumor and cell lines form very large H3K27ac-enriched super-enhancers that are unique to hNC, termed megadomains, that are invariably associated with key hNC-defining transcriptional oncogenic targets, Myc and Trp63.

2023-10-04 | GSE241474 | GEO

RNA-seq on NUT Carcinoma (NC) cell lines treated with DMSO, Panobinostat or IRBM6

Project description:HDAC inhibitor induce transcriptional program driving cellular differentiation and growth arrest in NUT Carcinoma (NC) cell lines TC-797 and 10-15.

2021-07-14 | GSE179693 | GEO

NSD3-NUT Fusion Oncoprotein in NUT Midline Carcinoma identified in 1221 patient-derived cell line by RNA-seq

Project description:Discarded live tumor tissue from a metastatic focus in the patientM-bM-^@M-^Ys lung was collected under institutional review board approval through the NUT midline carcinoma registry (www.NMCRegistry.org). From this tissue the first known NUT-variant cell line, 1221, was established. To determine the putative partner gene to NUT, we performed comprehensive RNA-sequencing on RNA purified from 1221. We identified an in-frame transcript fusing the 5M-bM-^@M-^Y coding sequence of NSD3 (exons 1-7) to exons 2-7 of NUT. Expression of the NSD3-NUT fusion oncoprotein was verified by immunobloting with an antibody to NUT, revealing an approximately 200kDa band that is similar in size to BRD3-NUT, but smaller than BRD4-NUT Identification of a NUT fusion partner using RNA extracted from live cultured 1221 cell line derived from a lung metastasis from the index case of a 13 year old female with NUT-positive NMC.

2014-08-01 | E-GEOD-57222 | biostudies-arrayexpress

Oncogenic BRD4-NUT protein interactions

Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.

2017-04-05 | PXD005786 | Pride

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