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

Abstract

Deleted in liver cancer (DLC) 1 and 2 are Rho GTPaseactivating 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]

Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease

“…Thus, deregulation of Rho activity is involved in oncogenic transformation of cells. 34 Accumulating evidence has recently indicated that DLC1 may act as a tumor suppressor by inhibiting Rho signaling. Moreover, loss of DLC1 expression has been clinically detected in many types of human tumors.…”

Functional Cross-talk between Ras and Rho Pathways

“…Fast kinetics (Ͻ1000 s) were performed with a Hi-Tech Scientific SF-61 stopped-flow instrument with a mercury xenon light source and TgK Scientific Kinetic Studio software (version 2. 19). An excitation wavelength of 545 nm was used for tamra.…”

Deleted in liver cancer protein family in human malignancies (Review)

“…However, little is known about the molecular mechanisms through which DLC family proteins are capable of suppressing cell motility and cell growth. In their study, Holeiter et al have shown that enhanced migration of cells lacking DLC1 is dependent on the Rho effector protein Dia1 and does not require the activity of Rho kinase (ROCK) (64). Leung et al provide evidence for a key mechanism through which DLC proteins act as tumor suppressors (65).…”