The Role Of FBXW2 In Regulation Of Migration And Invasion Of Lung Cancer Cells

FBXW2,an F-box ubiquitin ligase,acts as a tumor suppressor to inhibit growth and survival 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 a novel E3 for targeting oncogenic protein P-catenin.FBXW2 binds to ?-catenin upon EGF-AKT1-mediated phosphorylation on Ser552,and promotes its ubiquitylation and degradation.Ectopic FBXW2 expression reduces ?-catenin levels and its protein half-life,whereas siRNA-based FBXW2 knockdown increases P-catenin levels,protein half-life and transcriptional activity.Furthermore,FBXW2-mediated ?-catenin degradation is independent of?-TrCP1/GSK3?.Functionally,ectopic FBXW2 expression inhibits migration and invasion by blocking transactivation of MMPs driven by ?-catenin,whereas FXBW2 knockdown significantly promotes migration,invasion and metastasis both in vitro and in vivo lung cancer models.Mechanistic studies revealed that p-?-cateninSer552 preferentially binds to the TCF isoform TCF4M/S to activate the MMPs expression to regulate cell migration ans invasion,whereas the Wnt activated ?-catenin preferentially binds to the TCF isoform TCF4E to activate the MYC?CCND1 expression to regulate cell proliferation.Finally,in human lung cancer specimens,while FBXW2 levels are inversely correlated with(3-catenin levels and lymph-node metastasis,lower FBXW2 levels,coupled with higher ?-catenin levels,predict a worse patient survival.Collectively,our study revealed a novel function and associated mechanism by which FBXW2 inhibits tumor migration,invasion and metastasis in lung cancer cells by targeting ubiquitylation and degradation of ?-catenin.