Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP
- Yi Liu-Chittenden1,2,5,
- Bo Huang1,2,5,
- Joong Sup Shim3,
- Qian Chen1,2,
- Se-Jin Lee2,
- Robert A. Anders4,
- Jun O. Liu3 and
- Duojia Pan1,2,6
- 1Howard Hughes Medical Institute,
- 2Department of Molecular Biology and Genetics,
- 3Department of Pharmacology and Molecular Sciences,
- 4Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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↵5 These authors contributed equally to this work.
Abstract
The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD–YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD–YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
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Footnotes
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↵6 Corresponding author
E-mail djpan{at}jhmi.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.192856.112.
- Received March 26, 2012.
- Accepted May 11, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press