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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]

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: GSE202036 | GEO | 2023/10/01

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

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

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Project description:The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we report that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 develop enlarged livers and are prone to liver tumor formation. Transcriptomic profiling reveals that Yap1 reprograms genes involved in glutamine metabolism. Analysis of gene expression in WT and lf:Yap transgenic zebrafish livers.

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2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress

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Project description:The Hippo signaling pathway is evolutionarily well conserved, and all core components have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador), LATS1/2 (Warts), MOB1 (Mats), YAP1/TAZ (Yorkie), and TEAD1/2/3/4 (Scalloped) (Halder and Johnson, 2011; Pan, 2007; Dong et al., 2007; Saucedo and Edgar, 2007). When Hippo signaling is active, YAP1/TAZ is phosphorylated by LATS1/2 and sequestered by 14-3-3 proteins in cytoplasm. When Hippo signaling is absent, unphosphorylated YAP1/TAZ enters the nucleus and increases transcriptional activation of genes involved in cell proliferation and survival. The indispensability of the Hippo pathway in restricting cell growth and proliferation has prompted speculation that many members of the pathway might be involved in tumorigenesis. To see the effect of YAP1 and TAZ in HCC cell, we generated gene expression profile.

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Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.

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