Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.

TitleInhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.
Publication TypeJournal Article
Year of Publication2015
AuthorsYou B, Yang Y-L, Xu Z, Dai Y, Liu S, Mao J-H, Tetsu O, Li H, Jablons DM, You L
JournalOncotarget
Volume6
Issue6
Pagination4357-68
Date Published2015 Feb 28
ISSN1949-2553
KeywordsAdaptor Proteins, Signal Transducing, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Movement, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplasm Invasiveness, Phosphoproteins, Protein-Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Signal Transduction, Transfection
Abstract

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.

DOI10.18632/oncotarget.2974
Alternate JournalOncotarget
PubMed ID25738359
PubMed Central IDPMC4414195
Grant ListR01 CA140654 / CA / NCI NIH HHS / United States
R01 CA140654 / CA / NCI NIH HHS / United States