A Novel Function of YWHAZ/β-Catenin Axis in Promoting Epithelial-Mesenchymal Transition and Lung Cancer Metastasis

YWHAZ, also known as 14-3-3zeta, has been reportedly elevated in many human tumors, including non-small cell lung carcinoma (NSCLC) but little is known about its specific contribution to lung cancer malignancy. Through a combined array-based comparative genomic hybridization and expression microarray analysis, we identified YWHAZ as a potential metastasis enhancer in lung cancer. Ectopic expression of YWHAZ on low invasive cancer cells showed enhanced cell invasion, migration in vitro, and both the tumorigenic and metastatic potentials in vivo. Gene array analysis has indicated these changes associated with an elevation of pathways relevant to epithelial-mesenchymal transition (EMT), with an increase of cell protrusions and branchings. Conversely, knockdown of YWHAZ levels with siRNA or short hairpin RNA (shRNA) in invasive cancer cells led to a reversal of EMT. We observed that high levels of YWHAZ protein are capable of activating beta-catenin-mediated transcription by facilitating the accumulation of beta-catenin in cytosol and nucleus. Coimmunoprecipitation assays showed a decrease of ubiquitinated beta-catenin in presence of the interaction between YWHAZ and beta-catenin. This interaction resulted in disassociating beta-catenin from the binding of beta-TrCP leading to increase beta-catenin stability. Using enforced expression of dominant-negative and -positive beta-catenin mutants, we confirmed that S552 phosphorylation of beta-catenin increases the beta-catenin/YWHAZ complex formation, which is important in promoting cell invasiveness and the suppression of ubiquitnated beta-catenin. This is the first demonstration showing YWHAZ through its complex with beta-catenin in mediating lung cancer malignancy and beta-catenin protein stability. Mol Cancer Res; 10(10); 1319-31. (C) 2012 AACR.