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

Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12851-6. doi: 10.1073/pnas.1017372108. Epub 2011 Jul 18.


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 Ca(2+)/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Epithelial-Mesenchymal Transition*
  • Female
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microtubules / metabolism*
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • Serine / genetics
  • Serine / metabolism
  • Stathmin / genetics
  • Stathmin / metabolism*


  • Apoptosis Regulatory Proteins
  • SIVA1 protein, human
  • Stathmin
  • Serine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2