Abstract
The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, 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 superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release. Mechanistically, YAP interacts and recruits the Mediator complex to enhancers, allowing the 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 strategies for intervention.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Bile Duct Neoplasms / drug therapy
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Bile Duct Neoplasms / genetics*
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Bile Duct Neoplasms / metabolism
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Bile Duct Neoplasms / pathology
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Carcinogenesis / drug effects
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line, Tumor
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Cholangiocarcinoma / drug therapy
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Cholangiocarcinoma / genetics*
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Cholangiocarcinoma / metabolism
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Cholangiocarcinoma / pathology
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Chromatin / chemistry
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Chromatin / metabolism
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Cyclin-Dependent Kinase 9 / genetics
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Cyclin-Dependent Kinase 9 / metabolism
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DNA Polymerase II / genetics
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DNA Polymerase II / metabolism
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Enhancer Elements, Genetic
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic*
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Mediator Complex / genetics*
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Mediator Complex / metabolism
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Mice
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Mice, Transgenic
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Piperidines / pharmacology
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Protein Binding
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Signal Transduction
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Trans-Activators
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Transcription Factors
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Transcription, Genetic
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Chromatin
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Flavonoids
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Intracellular Signaling Peptides and Proteins
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Mediator Complex
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Phosphoproteins
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Piperidines
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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Wwtr1 protein, mouse
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YAP-Signaling Proteins
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YAP1 protein, human
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alvocidib
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CDK9 protein, human
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Cyclin-Dependent Kinase 9
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DNA Polymerase II