Sival suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules

摘要

Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesen-chymal cells. It plays an important role in development and tumor cell metastasis. However, the mechanisms of EMT and their dysfunction in cancer cells are still not well understood. Here we report that Sival interacts with stathmin, a microtubule destabilizer. Sival inhibits stathmin's activity directly as well as indirectly through Ca~(2+)/calmodulin-dependent protein kinase ll-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Sival enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Sival and Ser16-phosphorylated stathmin correlate with high met-astatic states of human breast cancer cells. In mouse models, knockdown of Sival promotes cancer dissemination, whereas overexpression of Sival inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Sival in suppressing cell migration and EMT and indicate that down-regulation of Sival may contribute to tumor cell metastasis.