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') 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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Blotting, Western, Carcinoma, Non-Small-Cell Lung, Casein Kinase II, Disease Models, Animal, Disease-Free Survival, Fluorescent Antibody Technique, Heterografts, Immunohistochemistry, Immunoprecipitation, Kaplan-Meier Estimate, Lung Neoplasms, Mice, Neoplasm Invasiveness, Repressor Proteins, Tissue Array Analysis
Cancer Res.
Date: Dec. 01, 2015
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