KIF3A binds to ?-arrestin for suppressing Wnt/?-catenin signalling independently of primary cilia in lung cancer.

ABSTRACT: Aberrant Wnt/?-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/?-catenin pathway components are uncommon in NSCLC, and their epigenetic control remains unclear. Here, we show that KIF3A, a member of the kinesin-2 family, plays a role in suppressing Wnt/?-catenin signalling in NSCLC cells. KIF3A knockdown increases both ?-catenin levels and transcriptional activity with concomitant promotion of malignant potential, such as increased proliferation and migration and upregulation of stemness markers. Because KIF3A binds ?-arrestin, KIF3A depletion allows ?-arrestin to form a complex with DVL2 and axin, stabilizing ?-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase ?-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as ?-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/?-catenin signalling and tumourigenesis in NSCLC.

SUBMITTER: Kim M 

PROVIDER: S-EPMC5011747 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature