Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells.
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.
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.|Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, People's Republic of China.
Bin
B
You
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Yi-Lin
YL
Yang
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Zhidong
Z
Xu
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Yuyuan
Y
Dai
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Shu
S
Liu
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA.
Jian-Hua
JH
Mao
Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, CA, USA.
Osamu
O
Tetsu
Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, People's Republic of China.
Hui
H
Li
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
David M
DM
Jablons
Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Liang
L
You
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014162:Transfection; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3