DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway

The DEAD-box RNA helicase DDX3 is a versatile protein involved in multiple steps of gene expression and various cellular signaling pathways. DDX3 mutations have been implicated in the wingless (Wnt) type of medulloblastoma. We show here that small interfering RNA-mediated DDX3 knockdown in various cell lines increased cell-cell adhesion but decreased cell-extracellular matrix adhesion. Moreover, DDX3 depletion suppressed cell motility and impaired directional migration in the wound-healing assay. Accordingly, DDX3-depleted cells exhibited reduced invasive capacities in vitro as well as reduced metastatic potential in mice. We also examined the mechanism underlying DDX3-regulated cell migration. DDX3 knockdown reduced the levels of both Rac1 and beta-catenin proteins, and consequentially downregulated the expression of several beta-catenin target genes. Moreover, we demonstrated that DDX3-regulated Rac1 mRNA translation, possibly through an interaction with its 5'-untranslated region, and affected beta-catenin protein stability in an Rac1-dependent manner. Taken together, our results indicate the DDX3-Rac1-beta-catenin regulatory axis in modulating the expression of Wnt/beta-catenin target genes. Therefore, this report provides a mechanistic context for the role of DDX3 in Wnt-type tumors.