FBXW2 suppresses migration and invasion of lung cancer cells via promoting β-catenin ubiquitylation and degradation

FBXW2 inhibits proliferation of lung cancer cells by targeting SKP2 for degradation. Whether and how FBXW2 regulates tumor invasion and metastasis is previously unknown. Here, we report that FBXW2 is an E3 ligase for beta-catenin. FBXW2 binds to beta-catenin upon EGF-AKT1-mediated phosphorylation on Ser(552), and promotes its ubiquitylation and degradation. FBXW2 overexpression reduces beta-catenin levels and protein half-life, whereas FBXW2 knockdown increases beta-catenin levels, protein half-life and transcriptional activity. Functionally, FBXW2 overexpression inhibits migration and invasion by blocking transactivation of MMPs driven by beta-catenin, whereas FXBW2 knockdown promotes migration, invasion and metastasis both in vitro and in vivo lung cancer models. In human lung cancer specimens, while FBXW2 levels are inversely correlated with beta-catenin levels and lymph-node metastasis, lower FBXW2 coupled with higher beta-catenin, predict a worse patient survival. Collectively, our study demonstrates that FBXW2 inhibits tumor migration, invasion and metastasis in lung cancer cells by targeting beta-catenin for degradation.