Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 31; pp. 12851 - 12856
• Main Authors: Li, Nan, Jiang, Peng, Du, Wenjing, Wu, Zhengsheng, Li, Cong, Qiao, Mengran, Yang, Xiaolu, Wu, Mian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.08.2011; National Acad Sciences
• Subjects: adhesion; Animal models; Animals; Antibodies; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological Sciences; Blotting, Western; Breast cancer; Breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Ca super(2+)/calmodulin-dependent protein kinase; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cell lines; Cell migration; Cell Movement; Cells; Epithelial cells; Epithelial-Mesenchymal Transition; Female; HEK293 Cells; Humans; Immunoprecipitation; Invasiveness; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubules; Microtubules - metabolism; neoplasm cells; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms, Experimental - genetics; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Phosphorylation; Protein Binding; RNA Interference; Rodents; Serine - genetics; Serine - metabolism; Small interfering RNA; stathmin; Stathmin - genetics; Stathmin - metabolism; Tumor cells; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1017372108

Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesenchymal 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 Siva1 interacts with stathmin, a microtubule destabilizer. Siva1 inhibits stathmin's activity directly as well as indirectly through Ca²⁺/calmodulin-dependent protein kinase II-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells. In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1 in suppressing cell migration and EMT and indicate that down-regulation of Siva1 may contribute to tumor cell metastasis.