AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition

Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor 0 (TGF0)-induced epithelial-mesen-chymal transition. Here, we report that nuclear deformation induced by TGF0 is concomitant with increased phosphorylation of lamin A at Ser390, defective nu-clear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGF0 to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGF0 stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGF0. These findings reveal a molecular mechanism for TGF0-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition.