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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

Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

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.

2016-08-02 | E-GEOD-82246 | biostudies-arrayexpress

Transcriptional targets of Hippo signaling in mammalian cells

Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.

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

The effect of YAP/TAZ knockdown on the intestinal epithelium

Project description:The Hippo pathway plays a crucial in organ size control during development and tissue homeostasis in adult life. To examine a role for Hippo signaling in the intestinal epithelium, we analyzed gene expression patterns in the mouse intestinal epithelilum transfected with siRNAs or expression plasmids for shRNAs targeting the Hippo pathway effectors, YAP and TAZ. We performed two independent series of experiments (siGFP (n=3) vs siYAP/siTAZ (n=3), and shLacZ (n=1) vs shYAP/shTAZ (n=1)). Control siRNA (siGFP), YAP/TAZ siRNAs, or expression plasmids for control shRNA (shLacZ) or YAP/TAZ shRNAs were introduced into the mouse intestinal epithelium by the newly-developed in vivo transfection method. Four days after transfection, intestinal epithelial cells were isolated from the tissues and total RNA was extracted.

2014-07-18 | E-GEOD-45155 | biostudies-arrayexpress

Regulation of gene expression by the Hippo effectors, Taz and Yap, in muscle stem cells

Project description:The Hippo pathway downstream effectors, Yap and Taz, play key roles in cell proliferation and tissue growth, regulating gene expression especially via interaction with Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analysed gene expression changes driven by Taz and compared these to Yap mediated changes to the transcriptome by measurement of gene expression on Affymetrix microarrays. To interrogate overlapping and unique transcriptional changes driven by these Hippo effectors, satellite cell-derived myoblasts were transduced with constitutively active TAZ S89A or YAP S127A retrovirus for 24h or 48h, with empty retrovirus as control. Triplicate microarray analyses of empty vector controls, hYAP1 S127A and TAZ S89A transgenic primary myoblasts were conducted.

2017-06-20 | E-MTAB-5395 | biostudies-arrayexpress

Yap/Taz inhibit goblet cell fate to maintain lung epithelial homeostasis

Project description:Proper lung function relies on precisely balanced numbers of specialized epithelial cell types that work together and are maintained in homeostasis. We describe essential roles for the transcriptional regulators Yap and Taz, which are key effectors of Hippo pathway signaling, in maintaining lung epithelial homeostasis. We report that conditional deletion of Yap1/Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects with consequent animal lethality. Phenotypes associated with Yap/Taz deletion include alveolar defects and a striking development of goblet cell metaplasia throughout the airways. We performed gene expression analysis of wild type and Yap/Taz null primary mouse airway epithelial cells in order to define Yap/Taz controlled gene expression.

2021-08-09 | GSE156525 | GEO

Gene espression Profile by YAP1 and TAZ

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.

2014-12-31 | GSE54617 | GEO

Gene espression Profile by YAP1 and TAZ

2014-12-31 | GSE54617 | GEO

DUB1 suppresses Hippo signaling via modulating TAZ protein in gastric cancer

Project description:The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer.

2022-02-12 | GSE196262 | GEO

YAP1 exerts its transcriptional control via TEAD mediated activation of enhancers

Project description:YAP is the principle effector of the Hippo signaling pathway; a key regulator of tissue homeostasis whose dysregulation is linked to cancer development. YAP regulation of gene expression is thought to involve the TEAD transcription factor family. Here we show that YAP and TEAD1 binding always co-occurs and is mediated by single as well as double TEAD1 motifs with a particular 3bp spacer (CATTCCNNNCATTCC). This suggests that YAP activity appears exclusively mediated by TEAD1. Despite being characterized as a promoter-binding factor YAP/TEAD actually binds predominantly to enhancers. Moreover we show that YAP is necessary for activity of the linked gene and proper chromatin state of regulated enhancers. These results establish mode of binding and activation of YAP mediated nuclear response of the Hippo pathway by TEAD1 and provide a comprehensive list and a novel class of direct target genes that are regulated distally and could be exploited for cancer therapeutics. Sequencing of ChIP and input samples for YAP1 and TEAD1 transcription factors and H3K27ac histone modification in SF268 glioblastoma cells and for YAP1 transcription factor in NCI-H2052 mesothelioma cells.

2015-08-25 | E-GEOD-61852 | biostudies-arrayexpress

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