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YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201714 | GEO | 2023/07/12

REPOSITORIES: GEO

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YAP1 maintains active chromatin state in head and neck squamous cell carcinomas that promotes tumorigenesis through cooperation with BRD4 [RNA-seq]

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.

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