Abstract
Rac1 activation is a common occurrence in various tumors and is often associated with poor prognosis, underscoring the potential therapeutic value of targeting the Rac1 pathway. Therefore, selectively inhibiting the heightened Rac1 activity in tumor cells may represent an innovative approach to cancer treatment. In this study, we found the increase in Rac1 expression contributes to heightened Rac1 activity and enhanced migration of HCC cells. Notably, our investigations identified FOXO6, rather than HIF-1α, Smad7, miR-142-3p, or miR-137, as the mediator of Rac1 expression. FOXO6 exhibits transcriptional activation and correlates with the early recurrence of HCC following hepatectomy. The transcriptional activation of the Rac1 gene hinges on a FOXO-binding sequence in the Rac1 gene promoter. FOXO6 was found to directly bind to this sequence both in vitro and in vivo. Ultimately, Rac1 operates downstream of the FOXO6-dependent pro-migration signaling cascade. Our findings illuminate the direct role of FOXO6 in mediating the upregulation of Rac1 expression and activity in HCC cells. This discovery unveils a differentially activated FOXO6/Rac1 pathway in liver cancer, thereby positioning FOXO6 as a potential therapeutic target for liver cancer treatment, offering the prospect of mitigating excessive side effects.