Abstract
The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.
Original language | English |
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Pages (from-to) | 273-287 |
Number of pages | 15 |
Journal | Cancer Cell |
Volume | 26 |
Issue number | 2 |
Early online date | 31 Jul 2014 |
DOIs | |
Publication status | Published - 11 Aug 2014 |
Keywords
- skeletal-muscle
- stem-cells
- gene-expression
- growth-control
- self-renewal
- differentiation
- transcription
- pathway
- MYOD
- quiescent
Profiles
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Cosimo de Bari
- Clinical Medicine
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Chair in Medicine & Therapeutics (Clinical)
- Institute of Medical Sciences
Person: Clinical Academic
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Graeme Murray
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Regius Chair of Pathology
- Clinical Medicine
- Institute of Medical Sciences
Person: Clinical Academic