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

Abstract

Aberrant Wnt/beta-catenin signalling is implicated in the progression of several human cancers, including non-small cell lung cancer (NSCLC). However, mutations in Wnt/beta-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/beta-catenin signalling in NSCLC cells. KIF3A knockdown increases both beta-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 beta-arrestin, KIF3A depletion allows beta-arrestin to form a complex with DVL2 and axin, stabilizing beta-catenin. Although primary cilia, whose biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibition of ciliogenesis failed to increase beta-catenin activity in NSCLC cells. A correlation between KIF3A loss and a poorer NSCLC prognosis as well as beta-catenin and cyclin D1 upregulation further suggests that KIF3A suppresses Wnt/beta-catenin signalling and tumourigenesis in NSCLC