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Deleted in Liver Cancer 1 Controls Cell Migration through a Dia1-Dependent Signaling Pathway

Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany

Requests for reprints: Monilola A. Olayioye, Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. Phone: 49-711-685-69301; Fax: 49-711-685-67484; E-mail: monilola.olayioye{at}izi.uni-stuttgart.de.

Key Words: cell motility • Rho GTPase-activating protein • actin cytoskeleton • signal transduction • tumor suppressor

Deleted in liver cancer (DLC) 1 and 2 are Rho GTPase-activating proteins that are frequently down-regulated in various types of cancer. Ectopic expression in carcinoma cell lines lacking these proteins has been shown to inhibit cell migration and invasion. However, whether the loss of DLC1 or DLC2 is the cause of aberrant Rho signaling in transformed cells has not been investigated. Here, we have down-regulated DLC1 and DLC2 expression in breast cancer cells using a RNA interference approach. Silencing of DLC1 led to the stabilization of stress fibers and focal adhesions and enhanced cell motility in wound-healing as well as chemotactic Transwell assays. We provide evidence that enhanced migration of cells lacking DLC1 is dependent on the Rho effector protein Dia1 but does not require the activity of Rho kinase. By contrast, DLC2 knockdown failed to affect the migratory behavior of cells, suggesting that the two proteins have distinct functions. This is most likely due to their differential subcellular localizations, with DLC1 found in focal adhesions and DLC2 being mainly cytosolic. Collectively, our data show that DLC1 is critically involved in the control of Rho signaling and actin cytoskeleton remodeling and that its cellular loss is sufficient for the acquisition of a more migratory phenotype of breast cancer cells. [Cancer Res 2008;68(21):8743–51]

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