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YAP drives proliferation and tumorigenesis by recruiting Mediator to super- enhancer elements (CClp1)

ABSTRACT: The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity. YAP is also a powerful driver of tumor growth and its nuclear accumulation is frequently observed in human cancer. However, the molecular mechanism employed by YAP to orchestrate transcriptional outputs are undefined. Here, we utilize genomic technologies to demonstrate that YAP occupancy is restricted to a small number of distal regulatory elements highly enriched for superenhancers. Target genes associated with these elements are selectively sensitive to the loss of YAP in cancer cells. YAP directs recruitment of the Mediator complex to activate transcriptional regulation from these enhancers without affecting chromatin organization We also provide in vivo genetic evidence that loss of Mediator rescues YAP-driven cancer cell proliferation and organ overgrowth. Our data provide a molecular mechanism behind YAP-driven tumorigenesis, and highlights transcriptional control as a potential therapeutic strategy for YAP-driven cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62272 | GEO | 2015/10/01

SECONDARY ACCESSION(S): PRJNA263636

REPOSITORIES: GEO

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YAP drives proliferation and tumorigenesis by recruiting Mediator to super- enhancer elements (H69)

Project description:The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity. YAP is also a powerful driver of tumor growth and its nuclear accumulation is frequently observed in human cancer. However, the molecular mechanism employed by YAP to orchestrate transcriptional outputs are undefined. Here, we utilize genomic technologies to demonstrate that YAP occupancy is restricted to a small number of distal regulatory elements highly enriched for superenhancers. Target genes associated with these elements are selectively sensitive to the loss of YAP in cancer cells. YAP directs recruitment of the Mediator complex to activate transcriptional regulation from these enhancers without affecting chromatin organization We also provide in vivo genetic evidence that loss of Mediator rescues YAP-driven cancer cell proliferation and organ overgrowth. Our data provide a molecular mechanism behind YAP-driven tumorigenesis, and highlights transcriptional control as a potential therapeutic strategy for YAP-driven cancers.

2017-10-10 | GSE62274 | GEO

YAP drives growth by controlling transcriptional pause release from dynamic enhancers (HuCCT1_siRNA)

Project description:The Hippo/YAP signaling pathway is a crucial regulator of tissue growth and stem cell activity.YAP, a transcriptional co-activator and main effector of the pathway, is also a powerful driver of tumorigenesis However, the genetic program regulated by YAP and the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP-occupancy defines a subset of enhancers and super-enhancers with the highest transcriptional outputs. We find that YAP modulates transcription from these elements predominantly by regulating promoter-proximal Polymerase II (PolII) pause release. Mechanistically, YAP physically interacts and recruits the Mediator complex to enhancers, which then allows for recruitment of the CDK9 elongating kinase. Genetic and chemical perturbation experiments demonstrate the requirement for Mediator and CDK9 in YAP-driven phenotypes of overgrowth and tumorigenesis. Our results here uncover the molecular mechanisms employed by YAP to exert its growth and oncogenic functions, and suggest new strategies for intervention.

2015-10-01 | GSE68388 | GEO

YAP drives growth by controlling transcriptional pause release from dynamic enhancers (HuCCT1)

2015-10-01 | GSE68296 | GEO

YAP drives growth by controlling transcriptional pause release from dynamic enhancers (MSTO)

2015-10-01 | GSE68170 | GEO

NUAK2 is a critical YAP target in liver cancer

Project description:The Hippo-YAP signaling pathway is a critical regulator of proliferation, apoptosis, and cell fate. The main downstream effector of this pathway, YAP, has been shown to be misregulated in human cancer and has emerged as an attractive target for therapeutics. A significant insufficiency in our understanding of the pathway is the identity of transcriptional targets of YAP that drive its potent growth phenotypes. Here, using liver cancer as a model, we identify NUAK2 as an essential mediator of YAP-driven hepatomegaly and tumorigenesis in vivo. By evaluating several human cancer cell lines we determine that NUAK2 is selectively required for YAP-driven growth. Mechanistically, we found that NUAK2 participates in a feedback loop to maximize YAP activity via promotion of actin polymerization and myosin activity. Additionally, pharmacological inactivation of NUAK2 suppresses YAP-dependent cancer cell proliferation and liver overgrowth. Importantly, our work here identifies a specific, potent, and actionable target for YAP-driven malignancies.

2018-10-18 | GSE107860 | GEO

A comprehensive enhancer screen identifies TRAM2 as a key mediator of YAP oncogenesis

Project description:Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated-YAP associates with enhancer loci via TEAD4-DNA-binding protein, and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites were annotated, their functional importance is unknow. Here, we implemented a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrated its robustness, and used it to reveal a network of enhancers required for YAP-mediated proliferation. We focused on Enhancer TRAM2, as its target gene TRAM2 showed the strongest expression-correlation with YAP in nearly all tumor types. Interestingly, TRAM2 phenocopied YAP-induced cell proliferation, migration and invasion phenotypes, and correlated with poor patient survival. Mechanistically, we identified FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness.

2021-01-14 | PXD018559 | Pride

Genome-wide analysis of YAP and TFCP2 binding DNA in liver cancer cells

Project description:To seek additional evidence that YAP closely interacts with TFCP2, we performed ChIP-seq assays in Bel-7402 cells using anti-TFCP2 or anti-YAP antibodies. We found that a subset of YAP binding regions overlapped with the TFCP2-occupied sites, suggesting that YAP- and TFCP2-regulated transcriptional outputs are likely correlated.

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The TAZ-CAMTA1 and YAP-TFE3 fusion proteins modulate the basal TAZ/YAP transcriptional program by recruiting the Ada2a-containing histone acetyltransferase complex [ChIP-seq]

Project description:The WWTR1(TAZ)-CAMTA1 and YAP1-TFE3 gene fusions are disease defining gene alterations for epithelioid hemangioendothelioma, a vascular cancer. The resultant fusion proteins fuse the C terminus of CAMTA1 and TFE3 in frame to the N terminus of TAZ and YAP, respectively. An unbiased BioID-mass spectrometry/RNAi screen identified YEATS2 and ZZZ3 as components of the Ada2a-containing histone acetyltransferase complex and key interactors of both TAZ-CAMTA1 and YAP-TFE3. An integrative NGS approach validating the chromatin occupancy of TAZ-CAMTA1 and YAP-TFE3 with distal regulatory elements, such as enhancer regions marked by the presence of H3K27ac marks. The altered transcriptional program of the fusion proteins owing to altered DNA binding as well as shifts in the chromatin landscape.

2021-03-04 | GSE168201 | GEO

Proteomics analysis of YAP knockdown in mouse skeletal muscle

Project description:Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis including proteomics from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

2021-02-25 | PXD024379 | Pride

YAP Inhibition in HCC cells (Hep3B)

Project description:siRNA-mediated inhibition compared to untreated cells and cells transfected with nonsense siRNA. Loss of contact inhibition and anchorage-independent growth are hallmarks of cancer cells. In this context, frequent inactivation of the Hippo pathway and subsequent nuclear enrichment of the transcriptional coactivator yes-associated protein (YAP) uncouple cell proliferation and anti-apoptosis from contact inhibition, associated with uncontrolled tumor growth and tumor cell dissemination. However, general molecular mechanisms of tumor-supporting YAP activity remain unclear. In this study, we show that overexpression and nuclear accumulation of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells leads to an induction of the Notch pathways through transcriptional activation of the Notch ligand jagged-1 (Jag-1). This induction of Jag-1 strictly depends on binding of YAP to TEAD4 and does not rely on WNT/β-catenin pathway activity. Co-activation of YAP, TEAD4, Jag-1, and the Notch target gene Hes-1 was significantly higher in HCC from patients with poor prognosis. High-level expression and nuclear accumulation of YAP correlates with Jag-1/Notch activation not only in human HCC tissues, but also in colon and pancreatic cancer tissues. Thus, our data demonstrate that YAP-driven co-activation of the Jag-1/Notch pathway in part facilitates oncogenic properties of the oncogene YAP not only in HCC but also in different gastrointestinal malignancies. Expression profiling of untreated HCC cell lines (control 1), cells transfected with scrambled/nonsense siRNA (control 2), and after siRNA-mediated YAP inhibition.

2012-11-01 | E-GEOD-35004 | biostudies-arrayexpress

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