Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness.
Oncogenes deregulate fundamental cellular functions, which can lead to development of tumors, tumor-cell invasion, and metastasis. As the mechanical properties of cells govern cell motility, we hypothesized that oncogenes promote cell invasion by inducing cytoskeletal changes that increase cellular stiffness. We show that the oncogenes simian virus 40 large T antigen, c-Myc, and cyclin E induce spatial reorganization of the vimentin intermediate filament network in cells. At the cellular level, this reorganization manifests as increased width of vimentin fibers and the collapse of the vimentin network. At nanoscale resolution, the organization of vimentin fibers in these oncogene-expressing cells was more entangled, with increased width of the fibers compared with control cells. Expression of these oncogenes also resulted in up-regulation of the tubulin deacetylase histone deacetylase 6 (HDAC6) and altered spatial distribution of acetylated microtubules. This oncogene expression also induced increases in cellular stiffness and promoted the invasive capacity of the cells. Importantly, HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of the oncogene-expressing cells. Taken together, these data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network.
Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Li-Sophie Z
LS
Rathje
Niklas
N
Nordgren
Torbjörn
T
Pettersson
Daniel
D
Rönnlund
Jerker
J
Widengren
Pontus
P
Aspenström
Annica K B
AK
Gad
D000107:Acetylation; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D009857:Oncogenes; D014746:Vimentin / Q000502:physiology*
D014746:Vimentin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
STED microscopy; cell invasion; cell mechanics; colloidal probe force-mode atomic force microscopy; cytoskeleton