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Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

2013; National Academy of Sciences; Volume: 111; Issue: 1 Linguagem: Inglês

10.1073/pnas.1319190110

1091-6490

Zhongyuan Wang, Yanping Wu, Haifeng Wang, Yangqing Zhang, Lin Mei, Xuexun Fang, Xudong Zhang, Fang Zhang, Hongbo Chen, Ying Liu, Yuyang Jiang, Shengnan Sun, Yi Zheng, Na Li, Laiqiang Huang,

Ubiquitin and proteasome pathways

Significance How receptor for hyaluronan-mediated motility (RHAMM) expression is regulated, how statins exert anticancer effects, and what roles mevalonate and Hippo pathways play in tumors are important issues in cancer biology. We find that the two pathways converge onto Yes-associated protein (YAP)/TEAD to control RHAMM transcription leading to ERK activation and cancer metastasis, which is inhibited by simvastatin. YAP/TEAD binds RHAMM promoter at specific sites to activate RHAMM transcription, and mevalonate/simvastatin affects RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic distribution. These in vitro and in vivo findings identify a mechanism regulating RHAMM expression and cancer metastasis wherein RHAMM is a downstream effector of mevalonate/Hippo pathways, and a YAP/TEAD-transcription and simvastatin-inhibition target, revealing interesting interplay of the pathways and potential targets for cancer therapeutic agents.