CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation
Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non-small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylatio...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2016-05, Vol.76 (9), p.2675-2686 |
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| creator | Liu, Yuan Amin, Elianna B Mayo, Marty W Chudgar, Neel P Bucciarelli, Peter R Kadota, Kyuichi Adusumilli, Prasad S Jones, David R |
| description | Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non-small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of S30 in BRMS1 or the use of the CK2-specific small-molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2α' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease-free survival. Collectively, we identify a therapeutically exploitable posttranslational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer. Cancer Res; 76(9); 2675-86. ©2016 AACR. |
| doi_str_mv | 10.1158/0008-5472.CAN-15-2888 |
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We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of S30 in BRMS1 or the use of the CK2-specific small-molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2α' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease-free survival. Collectively, we identify a therapeutically exploitable posttranslational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer. Cancer Res; 76(9); 2675-86. ©2016 AACR.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-15-2888</identifier><identifier>PMID: 26980766</identifier><language>eng</language><publisher>United States</publisher><subject>Active Transport, Cell Nucleus - physiology ; Animals ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Casein Kinase II - metabolism ; Disease Models, Animal ; Disease-Free Survival ; Fluorescent Antibody Technique ; Heterografts ; Immunohistochemistry ; Immunoprecipitation ; Kaplan-Meier Estimate ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mice ; Neoplasm Invasiveness - pathology ; Repressor Proteins - metabolism ; Tissue Array Analysis</subject><ispartof>Cancer research (Chicago, Ill.), 2016-05, Vol.76 (9), p.2675-2686</ispartof><rights>2016 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-47c00473cf50ec29743069e4621002db47f7ebf81b51259d0e5d156cd77739543</citedby><cites>FETCH-LOGICAL-c411t-47c00473cf50ec29743069e4621002db47f7ebf81b51259d0e5d156cd77739543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3343,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26980766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yuan</creatorcontrib><creatorcontrib>Amin, Elianna B</creatorcontrib><creatorcontrib>Mayo, Marty W</creatorcontrib><creatorcontrib>Chudgar, Neel P</creatorcontrib><creatorcontrib>Bucciarelli, Peter R</creatorcontrib><creatorcontrib>Kadota, Kyuichi</creatorcontrib><creatorcontrib>Adusumilli, Prasad S</creatorcontrib><creatorcontrib>Jones, David R</creatorcontrib><title>CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non-small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. 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Cancer Res; 76(9); 2675-86. ©2016 AACR.</description><subject>Active Transport, Cell Nucleus - physiology</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Casein Kinase II - metabolism</subject><subject>Disease Models, Animal</subject><subject>Disease-Free Survival</subject><subject>Fluorescent Antibody Technique</subject><subject>Heterografts</subject><subject>Immunohistochemistry</subject><subject>Immunoprecipitation</subject><subject>Kaplan-Meier Estimate</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Neoplasm Invasiveness - pathology</subject><subject>Repressor Proteins - metabolism</subject><subject>Tissue Array Analysis</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUctu2zAQJIIWsZvkExrw1l7kcilSpC4BXCV9ILYD5HUlKGrlKJAll5SC5rPyI_2mSIhrtMACi8XMzi5mCPkIbAYg9RfGmI6kUHyWzVcRyIhrrQ_IFGSsIyWEfEeme86EfAjhcRglMHlIJjxJNVNJMiX32SX_8_KJnvvqCQNd9M2aZrZx6OkSOxuGqgLNn-mt9WvsqgH-er28AbrqXY3W04vf29Z31DYFPce1t4XtqrY5Ju9LWwc82fUjcvft4jb7ES2uvv_M5ovICYAuEsoxJlTsSsnQ8VSJmCUpioQDY7zIhSoV5qWGXAKXacFQFiATVyil4lSK-Iicvelu-3yDhcOm87Y2W19trH82ra3M_0hTPZh1-2SEVrFgMAh83gn49lePoTObKjisa9tg2wcDKmUiAUj4QJVvVOfbEDyW-zPAzJiJGf02o99myMSANGMmw97pvz_ut_6GEL8CjjqHRQ</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Liu, Yuan</creator><creator>Amin, Elianna B</creator><creator>Mayo, Marty W</creator><creator>Chudgar, Neel P</creator><creator>Bucciarelli, Peter R</creator><creator>Kadota, Kyuichi</creator><creator>Adusumilli, Prasad S</creator><creator>Jones, David R</creator><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>5PM</scope></search><sort><creationdate>20160501</creationdate><title>CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation</title><author>Liu, Yuan ; 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We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of S30 in BRMS1 or the use of the CK2-specific small-molecule inhibitor CX4945 abrogates CK2α'-induced cell migration and invasion and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2α' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease-free survival. Collectively, we identify a therapeutically exploitable posttranslational mechanism by which CK2α-mediated degradation of BRMS1 promotes metastases in lung cancer. 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| subjects | Active Transport, Cell Nucleus - physiology Animals Blotting, Western Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Casein Kinase II - metabolism Disease Models, Animal Disease-Free Survival Fluorescent Antibody Technique Heterografts Immunohistochemistry Immunoprecipitation Kaplan-Meier Estimate Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice Neoplasm Invasiveness - pathology Repressor Proteins - metabolism Tissue Array Analysis |
| title | CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation |
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