Targeting YAP in malignant pleural mesothelioma

Wen Qian Zhang, Yu Yuan Dai, Ping Chih Hsu, Hui Wang, Li Cheng, Yi Lin Yang, Yu Cheng Wang, Zhi Dong Xu, Shu Liu, Geraldine Chan, Bin Hu, Hui Li, David M. Jablons, Liang You*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

55 Scopus citations

Abstract

Malignant mesothelioma is an aggressive cancer that is resistant to current therapy. The poor prognosis of mesothelioma has been associated with elevated Yes-associated protein (YAP) activity. In this study, we evaluated the effect of targeting YAP in mesothelioma. First, we comprehensively studied YAP activity in five mesothelioma cell lines (211H, H2052, H290, MS-1 and H2452) and one normal mesothelial cell line (LP9). We found decreased phospho-YAP to YAP protein ratio and consistently increased GTIIC reporter activity in 211H, H2052 and H290 compared to LP9. The same three cell lines (IC50s < 1 μM) were more sensitive than LP9 (IC50 = 3.5 μM) to the YAP/TEAD inhibitor verteporfin. We also found that verteporfin significantly reduced YAP protein level, mRNA levels of YAP downstream genes and GTIIC reporter activity in the same three cell lines, indicating inhibition of YAP signaling by verteporfin. Verteporfin also impaired invasion and tumoursphere formation ability of H2052 and H290. To validate the effect of specific targeting YAP in mesothelioma cells, we down-regulated YAP by siRNA. We found siYAP significantly decreased YAP transcriptional activity and impaired invasion and tumoursphere formation ability of H2052 and H290. Furthermore, forced overexpression of YAP rescued GTIIC reporter activity and cell viability after siYAP targeting 3′UTR of YAP. Finally, we found concurrent immunohistochemistry staining of ROCK2 and YAP (P < 0.05). Inhibition of ROCK2 decreased GTIIC reporter activity in H2052 and 211H suggesting that Rho/ROCK signaling also contributed to YAP activation in mesothelioma cells. Our results indicate that YAP may be a potential therapeutic target in mesothelioma.

Original languageEnglish
Pages (from-to)2663-2676
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume21
Issue number11
DOIs
StatePublished - 11 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Keywords

  • Hippo pathway
  • YAP
  • mesothelioma
  • therapeutic target

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