(The) role of KIF3A in the regulation of Wnt signaling in non-small cell lung cancer

Abstract

Aberrant $Wnt/ \beta -catenin$ signaling 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 epigenetic mechanisms controlling the Wnt/β-catenin pathway remain unclear. Here, we show that KIF3A, a member of the kinesin-2 motor family, plays a key role in suppressing $Wnt/ \beta -catenin$ signaling in NSCLC cells. Knockdown of KIF3A increases both $\beta -catenin$ levels and transcriptional activity, with a concomitant promotion of malignant phenotypes, such as enhanced proliferation and migration, and upregulation of stemness markers. KIF3A binds to $\beta -arrestin$, and KIF3A depletion allows $\beta -arrestin$ to form a complex with DVL2 and AXIN, resulting in $\beta -catenin$ stabilization. Although primary cilia, of which the biogenesis requires KIF3A, are thought to restrain the Wnt response, pharmacological inhibi-tion of ciliogenesis does not enhance $\beta -catenin$ activity in NSCLC cells. A correlation between KIF3A loss and worse NSCLC prognosis as well as upregulation of $\beta -catenin$ and Cyclin D1 further suggests that KIF3A is a suppressor of $Wnt/\beta -catenin$ signaling and tumorigenesis in NSCLC.