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

Abstract：

: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.

journal_name

Cancer Lett

journal_title

Cancer letters

authors

Tanaka K,Osada H,Murakami-Tonami Y,Horio Y,Hida T,Sekido Y

doi

10.1016/j.canlet.2016.10.020

subject

Has Abstract

pub_date

2017-01-28 00:00:00

pages

215-224

eissn

0304-3835

issn

1872-7980

pii

S0304-3835(16)30640-1

journal_volume

385

pub_type

杂志文章

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