YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients

PLoS One. 2014 Mar 12;9(3):e91770. doi: 10.1371/journal.pone.0091770. eCollection 2014.

Abstract

YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Carcinogenesis* / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Cisplatin / pharmacology
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Muscle Proteins / metabolism
  • Ovarian Neoplasms / diagnosis*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / pharmacology
  • Phosphoproteins / metabolism*
  • Prognosis
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Muscle Proteins
  • Phosphoproteins
  • TEAD4 protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Paclitaxel
  • Cisplatin

Grant support

This study was supported by the National Natural Science Foundation of China (81172473), the National Basic Research Program of China (2011CB944504, 2012CB944403), and Basic Scientific Research Funding of Zhejiang University (2011QN81001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.