title: CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation.
abstract: 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.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elianna B
authors.initials: EB
authors.lastname: Amin
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neel P
authors.initials: NP
authors.lastname: Chudgar
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bucciarelli
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. jonesd2@mskcc.org.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D047390:Casein Kinase II / Q000378:metabolism; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: C410024:BRMS1 protein, human; D012097:Repressor Proteins; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II