Therapeutic targeting of BRD4 in head neck squamous cell carcinoma
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ABSTRACT:
PROVIDER: PRJNA505480 | ENA |
REPOSITORIES: ENA
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Project description:Sage performed on microdissection of Head and Neck tumor, and Head and Neck normal tissue comparative analysis of gene expression profiles of head and neck squamous cell carcinoma and Head and Neck normal tissue
2008-09-30 | E-GEOD-11986 | biostudies-arrayexpress
Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of public available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regualted genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Our findings reveal that BRD4 serves as a novel oncogene driving cancer progression and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.
2019-05-09 | GSE122522 | GEO
Project description:The differential diagnosis between head & neck squamous cell carcinomas and lung squamous cell carcinomas is often unresolved because the histologic appearance of these two tumor types is similar. In the development of a gene expression profile test (GEP-HN-LS) that distinguishes these 2 cancer types, a collection of poorly differentiated primary and metastatic tumor specimens were used. Here we describe 76 such tumor specimens that were used for validation of GEP-HN-LS. The specimens are either head & neck squamous cell carcinomas or lung squamous cell carcinomas.
2013-03-10 | GSE44170 | GEO
Project description:The differential diagnosis between head & neck squamous cell carcinomas and lung squamous cell carcinomas is often unresolved because the histologic appearance of these two tumor types is similar. In the development of a gene expression profile test (GEP-HN-LS) that distinguishes these 2 cancer types, a collection of poorly differentiated primary and metastatic tumor specimens were used. Here we describe 76 such tumor specimens that were used for validation of GEP-HN-LS. The specimens are either head & neck squamous cell carcinomas or lung squamous cell carcinomas. All tissue specimens were formalin fixed paraffin embedded specimens. Gene expression was profiled using Affymetrix GeneChip platform.
2013-03-10 | E-GEOD-44170 | biostudies-arrayexpress
Project description:The conserved Hippo-YAP signaling pathway is involved in homeostasis and organ development through the regulation of cell growth and cell death. Its downstream effectors YAP1, WWTR1 (TAZ), and TEAD are transcriptionally active in the majority of human cancers, often as a result of copy-number variation or inactivating mutations of core components and upstream regulators. Analysis of The Cancer Genome Atlas and other published data of head and neck squamous cell carcinoma (HNSCC) reveals somatic alterations of the Hippo-YAP pathway in approximately 50% of HNSCC, making it the most altered pathway in these cancers. Unfortunately, highly specific inhibitors targeting the YAP1 transcriptional complex are not available, and better strategies to target this pathway are sought. Here, we show that FAT1 (FAT Atypical Cadherin 1), an upstream inhibitor of YAP1, is mutated either by missense or truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibit selective and higher sensitivity to BRD4 inhibition by JQ1. Epigenomic analysis reveals an active chromatin state in FAT1-mutant HNSCC cells that is driven by the YAP/TAZ transcriptional complex through recruitment of BRD4 to deposit active histone marks, thereby maintaining an oncogenic transcriptional state. This study reveals a detailed cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for the treatment of this subset of head and neck cancer patients.
2023-07-12 | GSE201714 | GEO
Project description:Monitoring of changes in the proteomic composition of extracellular vesicles produced by head and neck squamous cell carcinoma cells after exposure to agents affecting autophagic and lysosomal processes. LC-MS analysis of phosphatidylserine-positive budding EVs.
2023-05-25 | PXD037164 | Pride
Project description:The conserved Hippo-YAP signaling pathway is involved in homeostasis and organ development through the regulation of cell growth and cell death. Its downstream effectors YAP1, WWTR1 (TAZ), and TEAD are transcriptionally active in the majority of human cancers, often as a result of copy-number variation or inactivating mutations of core components and upstream regulators. Analysis of The Cancer Genome Atlas and other published data of head and neck squamous cell carcinoma (HNSCC) reveals somatic alterations of the Hippo-YAP pathway in approximately 50% of HNSCC, making it the most altered pathway in these cancers. Unfortunately, highly specific inhibitors targeting the YAP1 transcriptional complex are not available, and better strategies to target this pathway are sought. Here, we show that FAT1 (FAT Atypical Cadherin 1), an upstream inhibitor of YAP1, is mutated either by missense or truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibit selective and higher sensitivity to BRD4 inhibition by JQ1. Epigenomic analysis reveals an active chromatin state in FAT1-mutant HNSCC cells that is driven by the YAP/TAZ transcriptional complex through recruitment of BRD4 to deposit active histone marks, thereby maintaining an oncogenic transcriptional state. This study reveals a detailed cooperative mechanism between YAP1 and BRD4 in HNSCC and suggests a specific therapeutic opportunity for the treatment of this subset of head and neck cancer patients.
2023-10-01 | GSE202036 | GEO
Project description:Gene Expression Analysis of Squamous Cell Carcinoma of Head and Neck
2008-06-12 | E-GEOD-2326 | biostudies-arrayexpress
Project description:We report single cell transcriptome data from HPV-positive head and neck squamous cell carcinoma patients
2023-06-20 | GSE173468 | GEO
Project description:We show that head and neck squamous cell carcinomas models with deficient H3K36me, induced by H3K36M expression, lead to epigenetic dysregulation.
2024-01-02 | GSE222312 | GEO