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Persistent hyperactivity of the Hippo effector YAP in activated satellite cells is sufficient to cause embryonal rhabdomyosarcoma (ERMS) in mice. In humans, YAP is abundant and nuclear in the majority of ERMS cases, and high YAP expression is associated with poor survival. However,  YAP1  is rarely mutated in human ERMS. Instead, the most common mutations in ERMS are oncogenic RAS mutations. First, to compare  YAP1   S127A  and  KRAS   G12V -driven rhabdomyosarcomas, we re-analysed gene expression microarray datasets from mouse rhabdomyosarcomas caused by these genes. This revealed that only 20% of the up or downregulated genes are identical, suggesting substantial differences in gene expression between YAP and KRAS-driven rhabdomyosarcomas. As oncogenic RAS has been linked to YAP in other types of cancer, we also tested whether  KRAS G12V  alone or in combination with loss of  p53  and  p16  activates YAP in myoblasts. We found that neither  KRAS G12V  alone nor  KRAS G12V  combined with loss of  p53  and  p16  activated Yap or Yap/Taz-Tead1–4 transcriptional activity in C2C12 myoblasts or U57810 cells. In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of  KRAS G12V  expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between  KRAS G12V  and  YAP1 S127A -driven tumours.

Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma