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

• Published in: Cell reports (Cambridge) Vol. 39; no. 11; p. 110970
• Main Authors: Chen, Nana, Golczer, Gabriel, Ghose, Subhoshree, Lin, Brian, Langenbucher, Adam, Webb, Jason, Bhanot, Haymanti, Abt, Nicholas B., Lin, Derrick, Varvares, Mark, Sattler, Martin, Egloff, Ann Marie, Joh, Richard, Uppaluri, Ravindra, Emerick, Kevin S., Lawrence, Michael S., Saladi, Srinivas Vinod
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.06.2022; Elsevier
• Subjects: ATAD2; BRD4; CP: Cancer; CP: Molecular biology; FAT1 mutation; hippo pathway; HNSCC; JQ1; NRG1; OTX-015; PD-L1; YAP1; YAP1; hippo pathway; HNSCC; CP: Cancer; ATAD2; PD-L1; CP: Molecular biology; OTX-015; NRG1; JQ1; FAT1 mutation; BRD4
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110970

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. Better strategies to target the YAP1 transcriptional complex are sought. Here, we show that FAT1, an upstream inhibitor of YAP1, is mutated either by missense or by truncating mutation in 29% of HNSCC. Comprehensive proteomic and drug-screening studies across pan-cancer models confirm that FAT1-mutant HNSCC exhibits 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. [Display omitted] •FAT1 mutation contributes to YAP1 transcriptional activation•FAT1-mutant HNSCC exhibits selective and higher sensitivity to BRD4 inhibition•YAP1/TAZ/TEAD transcriptional complex recruits BRD4 to promote active chromatin state•YAP1 and BRD4 regulate multiple oncogenic transcriptional programs in HNSCC Chen et al. report that FAT1 mutation contributes to YAP1 transcriptional activation and exhibits selective sensitivity to BRD4 inhibitors. Mechanistically, YAP1-driven oncogenic chromatin state in FAT1-mutant HNSCC is through recruitment of BRD4. This study suggests BRD4 inhibitors as a therapeutic opportunity for FAT1-mutant HNSCC patients.