Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells
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Bin You1,2,*, Yi-Lin Yang1,*, Zhidong Xu1, Yuyuan Dai1, Shu Liu1, Jian-Hua Mao3, Osamu Tetsu4, Hui Li2, David M. Jablons1, Liang You1
1Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
2Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, People's Republic of China
3Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA
4Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco, CA, USA
*These authors have contributed equally to this work
Liang You, e-mail: [email protected]
Keywords: non-small cell lung cancer, extracellular signal regulated kinases, Hippo pathway, yes-associated protein, inhibition
Received: June 17, 2014 Accepted: December 20, 2014 Published: January 23, 2015
Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3'UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells.
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