Differentiation-inducing factor-1 inhibits EMT by proteasomal degradation of TAZ and YAP in cervical and colon cancer cell lines.

We previously reported differentiation-inducing factor-1 (DIF-1) activated glycogen synthase kinase-3 (GSK-3) in various mammalian cells. GSK-3 has been proposed to regulate a number of signaling pathway including TAZ/YAP signaling pathway. To clarify the effect of DIF-1 on TAZ/YAP signaling pathway, we examined whether DIF-1 affect the expression levels of TAZ and YAP. We found that DIF-1-induced proteasomal- and GSK-3-dependent degradation of both TAZ and YAP in human cervical cancer cell line HeLa in a time- and dose-dependent manner. As TAZ/YAP signaling pathway is well known to accelerate the epithelial-mesenchymal transition (EMT) of the cancer cell, we examined the effect of TAZ/YAP signaling pathway on EMT-related proteins. Knockdown of TAZ and YAP proteins by siRNA significantly reduced the expression of fibronectin, vimentin, and Snail. We also found that DIF-1 suppressed the expression levels of TAZ/YAP target gene products and EMT-related protein. Further, overexpression of TAZ and YAP attenuated the inhibitory effects of DIF-1 on these protein expressions. Migration and trans-well invasion assays revealed that DIF-1 significantly inhibited HeLa cell migration and invasion. DIF-1-induced proteasomal- and GSK-3-dependent degradation of TAZ and YAP proteins and inhibition of cell migration and invasion were also observed in human colon cancer cell line HCT-116. These results suggest that DIF-1 inhibits the TAZ/YAP signaling pathway via GSK-3 activation. Further, it has been suggested that the inhibition of EMT induced by DIF-1 is involved with the suppression of TAZ/YAP signaling pathway.