The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion.

The Cut homeobox gene 1 (CUX1) codes for several homeodomain proteins that display distinct DNA binding and transcriptional properties. Some CUX1 isoforms were previously shown to stimulate entry into S phase. More recently, siRNA-mediated knockdown of CUX1 was shown to cause a decrease in cell migration and invasion. In contrast, ectopic expression of p110 or p75 CUX1 stimulated cell migration and invasion in tissue culture. Moreover, metastasis to the lung was observed in a few cases following development of mammary tumors in p75 CUX1 transgenic mice. Chromatin immunoprecipitation (ChIP) assays followed by hybridization on promoter arrays (ChIP-chip) led to the identification of more than 20 genes that are directly regulated by CUX1 and code for proteins involved in cytoskeleton remodeling, cell-cell and cell-matrix adhesion, epithelial to mesenchymal transition and transcriptional regulation. Many targets of CUX1 are regulators of Rho GTPases that play a role both in cell cycle progression and cell motility. Interestingly, some genes that promote cell motility are activated by CUX1, while some genes that inhibit cell motility are repressed by CUX1. The dual function of CUX1 as an activator and repressor is best exemplified by the regulatory cascade whereby CUX1 activates expression of the Snail and Slug transcription factors and then cooperates with them to repress the E-cadherin and occludin genes, thereby causing a severe disorganization of cell-cell junctions. Together, these studies indicate that CUX1 stimulates cell motility by regulating a large number of genes involved in various molecular functions.