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YAP1 exerts its transcriptional control via TEAD-mediated activation of enhancers

ABSTRACT: YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61852 | GEO | 2015/08/25

SECONDARY ACCESSION(S): PRJNA262557

REPOSITORIES: GEO

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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

Conditional expression of sh-YAP1 modulates YAP1/TEAD-dependent transcription and causes regression of established human malignant mesothelioma MSTO-211H [sh-YAP1] xenografts.

Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196672 | GEO

Activation of hepatocyte growth factor (HGF)/MET signaling as a mechanism of acquired resistance to a novel YAP1/TEAD small molecule inhibitor.

Project description:Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily (BID) oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. Additionally, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A demonstrating potent and specific inhibition of YAP1/TAZ-TEAD mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.

2024-03-26 | GSE249903 | GEO

Conditional expression of a dominant negative-TEAD2 construct modulates YAP1/TEAD-dependent transcription and arrests growth of human malignant mesothelioma MSTO-211H [TEAD2-dn] xenografts.

Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, expression of a dominant negative TEAD2 modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, TEAD2 activity is essential to maintain the growth of mesothelioma tumors in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196691 | GEO

The Hippo tranducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation

Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background

2014-08-12 | E-GEOD-55186 | biostudies-arrayexpress

Lysine long-chain fatty acylation regulates the TEAD transcription factor

Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.

2023-03-19 | PXD033939 | Pride

A non-canonical role of YAP/TEAD is required for activation of estrogen-regulated enhancers in breast cancer [GRO-seq]

Project description:Estrogen and estrogen receptor alpha (ERα) signaling plays an essential role in ERα-positive breast cancer. ERα mainly occupies on distal enhancers within genome and requires the cooperation of additional co-factors to tune the enhancer activity. Through in vivo proximity-dependent labeling technique BioID, we identified YAP1 and TEAD4 protein as novel co-regulators of ERα. YAP and TEAD are nuclear effectors of the Hippo pathway regulating cell proliferation, organ size and tumorigenesis. Their non-canonical function as transcriptional co-regulators for other signals have been reported but remains under investigated. Our ChIP-seq data in both MCF7 and T47D breast cancer cell lines indicated that YAP1 and TEAD4 co-bind to the strongest estrogen-responsive ERα-bound enhancers, and their bindings are augmented upon E2 stimulation. Knockdown of YAP1 or TEAD4 showed a global effect on the induction of E2/ERα target genes as examined by RNA-seq, also on E2-induced oncogenic growth of ER-positive breast cancer cells. We used Global Run-on sequencing (GRO-seq) assays to test the expression of enhancer non-coding RNAs (eRNAs), which are sensitive markers for estrogen-induced enhancer activation. Our results supported our hypothesis that the recruitment YAP/TEAD to ERα-bound enhancers is required for enhancer activation. Further studies revealed that the binding of YAP1 on ERα enhancers is a prerequisite for the recruitment of the enhancer activation machinery component MED1. These findings indicate that ERα collaborates with YAP1 and TEAD4 to activate or maintain its enhancer activity. Our data reveals a non-canonical function of YAP1 and TEAD4, which is independent of their canonical target genes, in regulating cancer growth, highlighting the potential of YAP1 and TEAD4 as actionable drug targets for ERα-positive breast cancer.

2019-07-16 | GSE125607 | GEO

A non-canonical role of YAP/TEAD is required for activation of estrogen-regulated enhancers in breast cancer [ChIP-seq]

2019-07-16 | GSE125594 | GEO

A non-canonical role of YAP/TEAD is required for activation of estrogen-regulated enhancers in breast cancer [RNA-seq]

2019-07-16 | GSE125606 | GEO

Human malignant mesothelioma NCI-H226 cells treated with TEAD inhibitor K-975 in SCID mice.

Project description:We investigate the dependence of human malignant mesothelioma on functional TEAD transcription factors to maintain fully established tumors in vivo. We show that TEAD inhibitor K-975 stops tumor growth in vivo, eventually causing tumor regression, by downregulating TEAD activity and altering, thus, TEAD-dependent transcription in a dysfunctional Hippo genetic background. Our data validate the concept of inhibiting an activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196726 | GEO

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