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 lev...
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| Veröffentlicht in: | Oncotarget 2015-02, Vol.6 (6), p.4357-4368 |
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| creator | You, Bin Yang, Yi-Lin Xu, Zhidong Dai, Yuyuan Liu, Shu Mao, Jian-Hua Tetsu, Osamu Li, Hui Jablons, David M You, Liang |
| description | 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. |
| doi_str_mv | 10.18632/oncotarget.2974 |
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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.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.2974</identifier><identifier>PMID: 25738359</identifier><language>eng</language><publisher>United States: Impact Journals</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Biology ; Cell Line, Tumor ; Cell Movement - physiology ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Neoplasm Invasiveness - pathology ; Oncology ; Phosphoproteins - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Real-Time Polymerase Chain Reaction ; Research Paper ; RNA, Small Interfering ; Signal Transduction - physiology ; Transcription Factors ; Transfection</subject><ispartof>Oncotarget, 2015-02, Vol.6 (6), p.4357-4368</ispartof><rights>Copyright: © 2015 You et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c489t-47cc2cd6ea4dcd1a6111bb041dfdb29d265d7fcca11fbe16dc18db1f5511c9573</citedby><cites>FETCH-LOGICAL-c489t-47cc2cd6ea4dcd1a6111bb041dfdb29d265d7fcca11fbe16dc18db1f5511c9573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414195/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414195/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25738359$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1627983$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>You, Bin</creatorcontrib><creatorcontrib>Yang, Yi-Lin</creatorcontrib><creatorcontrib>Xu, Zhidong</creatorcontrib><creatorcontrib>Dai, Yuyuan</creatorcontrib><creatorcontrib>Liu, Shu</creatorcontrib><creatorcontrib>Mao, Jian-Hua</creatorcontrib><creatorcontrib>Tetsu, Osamu</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Jablons, David M</creatorcontrib><creatorcontrib>You, Liang</creatorcontrib><title>Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>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.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - physiology</subject><subject>Down-Regulation</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Neoplasm Invasiveness - pathology</subject><subject>Oncology</subject><subject>Phosphoproteins - metabolism</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Research Paper</subject><subject>RNA, Small Interfering</subject><subject>Signal Transduction - physiology</subject><subject>Transcription Factors</subject><subject>Transfection</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1r3DAQFaWhCWnuPRXRUy_OemTJti6FsKRN6NKEfkB7EvJItlW8kmvJDfn38WbTNJnLDMybN-_xCHkD-SnUZcFWwWNIeupsOmWy4i_IEUguMyZE8fLJfEhOYvydLyV4VTP5ihwyURV1IeQR-Xnpe9e45IKnoaXnXz_DilETbnw22W4edLKRpt7SCzeOYfXr7JpG13k9ON_RUaf-Rt9S52k_b7WnX76tN2uKdhjia3LQ6iHak4d-TH58PP--vsg2V58u12ebDHktU8YrRIamtJobNKBLAGianINpTcOkYaUwVYuoAdrGQmkQatNAKwQAysXGMfmw5x3nZmsNWp8mPahxcls93aqgnXq-8a5XXfirOAcOUiwE7_YEISanIrpkscfgvcWkoGSVrIsF9P7hyxT-zDYmtXVx51N7G-a44EpeVWVR7ATleyhOIcbJto9aIFf3wan_waldcMvJ26ceHg_-xVTcAa_Sl4w</recordid><startdate>20150228</startdate><enddate>20150228</enddate><creator>You, Bin</creator><creator>Yang, Yi-Lin</creator><creator>Xu, Zhidong</creator><creator>Dai, Yuyuan</creator><creator>Liu, Shu</creator><creator>Mao, Jian-Hua</creator><creator>Tetsu, Osamu</creator><creator>Li, Hui</creator><creator>Jablons, David M</creator><creator>You, Liang</creator><general>Impact Journals</general><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20150228</creationdate><title>Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells</title><author>You, Bin ; Yang, Yi-Lin ; Xu, Zhidong ; Dai, Yuyuan ; Liu, Shu ; Mao, Jian-Hua ; Tetsu, Osamu ; Li, Hui ; Jablons, David M ; You, Liang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c489t-47cc2cd6ea4dcd1a6111bb041dfdb29d265d7fcca11fbe16dc18db1f5511c9573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - physiology</topic><topic>Down-Regulation</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Neoplasm Invasiveness - pathology</topic><topic>Oncology</topic><topic>Phosphoproteins - metabolism</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Research Paper</topic><topic>RNA, Small Interfering</topic><topic>Signal Transduction - physiology</topic><topic>Transcription Factors</topic><topic>Transfection</topic><toplevel>online_resources</toplevel><creatorcontrib>You, Bin</creatorcontrib><creatorcontrib>Yang, Yi-Lin</creatorcontrib><creatorcontrib>Xu, Zhidong</creatorcontrib><creatorcontrib>Dai, Yuyuan</creatorcontrib><creatorcontrib>Liu, Shu</creatorcontrib><creatorcontrib>Mao, Jian-Hua</creatorcontrib><creatorcontrib>Tetsu, Osamu</creatorcontrib><creatorcontrib>Li, Hui</creatorcontrib><creatorcontrib>Jablons, David M</creatorcontrib><creatorcontrib>You, Liang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>You, Bin</au><au>Yang, Yi-Lin</au><au>Xu, Zhidong</au><au>Dai, Yuyuan</au><au>Liu, Shu</au><au>Mao, Jian-Hua</au><au>Tetsu, Osamu</au><au>Li, Hui</au><au>Jablons, David M</au><au>You, Liang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-02-28</date><risdate>2015</risdate><volume>6</volume><issue>6</issue><spage>4357</spage><epage>4368</epage><pages>4357-4368</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><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.</abstract><cop>United States</cop><pub>Impact Journals</pub><pmid>25738359</pmid><doi>10.18632/oncotarget.2974</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Biology Cell Line, Tumor Cell Movement - physiology Down-Regulation Gene Expression Regulation, Neoplastic Humans Immunohistochemistry Lung Neoplasms - metabolism Lung Neoplasms - pathology Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Neoplasm Invasiveness - pathology Oncology Phosphoproteins - metabolism Protein-Serine-Threonine Kinases - metabolism Real-Time Polymerase Chain Reaction Research Paper RNA, Small Interfering Signal Transduction - physiology Transcription Factors Transfection |
| title | Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells |
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