YAP1 activation promotes epithelial-mesenchymal transition and cell survival of renal cell carcinoma cells under shear stress

Abstract

Renal cell carcinoma (RCC) is characterized by substantial vasculatures and increased fluid movement in tumor microenvironment, and the fluid shear stress modulates malignance, extravasation and metastatic seeding of tumor cells. However, the precise mechanism remains largely unclear. In this study, we found that low shear stress induced the Yes-associated protein (YAP1) activation and nuclear localization in RCC cells, as well as the downregulation of phosphorylated YAP1 at Ser127. Moreover, inhibition of ROCK or RhoA partially abolished YAP1 accumulation in the nucleus, and targeting YAP1 activation by small molecular inhibitor or genetic manipulation decreased the low shear stress-induced epithelial-mesenchymal transition (EMT) of RCC cells, and led to a decreased expression of N-cadherin as accompanied by downregulation of SNAIL1 and TWIST, accompanied by high shear stress-induced cell apoptosis. Salvianolic acid B, an aqueous component of danshen (Salvia miltiorrhiza), inhibited YAP1 and Hippo signaling activation, and abrogated low shear stress-induced EMT as a consequence. Taken together, our study suggests YAP1 is a fluid mechanosensor that transforms mechanical stimuli to cell signals, thereby facilitates anoikis resistance and tumor metastasis.