The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation

Cancer Cell. 2014 Aug 11;26(2):273-87. doi: 10.1016/j.ccr.2014.05.029. Epub 2014 Jul 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • DNA-Binding Proteins / metabolism
  • Gene Dosage
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Muscle Neoplasms / metabolism*
  • Muscle Neoplasms / mortality
  • Muscle Neoplasms / pathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • MyoD Protein
  • Neoplasm Transplantation
  • Nuclear Proteins / metabolism
  • Oncogenes
  • Phosphoproteins / physiology*
  • Rhabdomyosarcoma, Embryonal / metabolism*
  • Rhabdomyosarcoma, Embryonal / mortality
  • Rhabdomyosarcoma, Embryonal / pathology
  • Satellite Cells, Skeletal Muscle / pathology*
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Nuclear Proteins
  • Phosphoproteins
  • TEAD1 protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human