論文

査読有り
2017年1月

Statin suppresses Hippo pathway-inactivated malignant mesothelioma cells and blocks the YAP/CD44 growth stimulatory axis

CANCER LETTERS
  • Kosuke Tanaka
  • ,
  • Hirotaka Osada
  • ,
  • Yuko Murakami-Tonami
  • ,
  • Yoshitsugu Horio
  • ,
  • Toyoaki Hida
  • ,
  • Yoshitaka Sekido

385
開始ページ
215
終了ページ
224
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.canlet.2016.10.020
出版者・発行元
ELSEVIER IRELAND LTD

Malignant mesothelioma (MM) frequently exhibits Hippo signaling pathway inactivation (HPI) mainly due to NF2 and/or LATS2 mutations, which leads to the activation of YAP transcriptional co-activator. Here, we show antitumor effects of statin on MM cells with HPI, through the interplay of the mevalonate and Hippo signaling pathways. Statin attenuated proliferation and migration of MM cells harboring NF2 mutation by accelerating YAP phosphorylation/inactivation. CD44 expression was decreased by statin, in parallel with YAP phosphorylation/inactivation. Importantly, we discovered that YAP/TEAD activated CD44 transcription by binding to the CD44 promoter at TEAD-binding sites. On the other hand, CD44 regulated Merlin phosphorylation according to cell density and sequentially promoted YAP transcriptional co-activator, suggesting that CD44 plays two pivotal functional roles as an upstream suppressor of the Hippo pathway and one of downstream targets regulated by YAP/TEAD. Moreover, the YAP/CD44 axis conferred cancer stem cell (CSC)-like properties in MM cells leading to chemoresistance, which was blocked by statin. Together, our findings suggest that YAP mediates CD44 up-regulation at the transcriptional level, conferring CSC-like properties in MM cells, and statin represents a potential therapeutic option against MM by inactivating YAP. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Web of Science ® 被引用回数 : 29

リンク情報
DOI
https://doi.org/10.1016/j.canlet.2016.10.020
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/27773750
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000390496400025&DestApp=WOS_CPL

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