The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in <i>KRAS</i>-wild-type colorectal cancer

Abstract

The mechanism underlying tumor aggressiveness and cetuximab (CTX) resistance in <i>KRAS</i>-wild-type (<i>KRAS</i> -WT) colorectal cancer remains obscure. We here provide evidence that DDX3 promoted soft agar growth and invasiveness of <i>KRAS</i>-WT cells, as already confirmed in <i>KRAS</i>-mutated cells. Mechanistically, increased KRAS expression induced ROS production, which elevated HIF-1α and YAP1 expression. Increased HIF-1α persistently promoted DDX3 expression via a KRAS/ROS/HIF-1α feedback loop. DDX3-mediated aggressiveness and CTX resistance were regulated by the YAP1/SIX2 axis in <i>KRAS</i>-WT cells and further confirmed in animal models. Kaplan-Meier and Cox regression analysis indicated that DDX3, KRAS, and YAP1 expression had prognostic value for OS and RFS in <i>KRAS</i>-WT and <i>KRAS</i>-mutated tumors, but SIX2 and YAP1/SIX2 were prognostic value only in <i>KRAS</i>-WT patients. The observation from patients seemed to support the mechanistic action of cell and animal models. We therefore suggest that combining YAP1 inhibitors with CTX may therefore suppress DDX3-mediated tumor aggressiveness and enhance CTX sensitivity in <i>KRAS</i>-WT colorectal cancer.