Downregulation of E-cadherin is a frequent event in epithelial cancers, and it correlates with weakened cell-cell adhesion, and an epithelial-to-mesenchymal transition (EMT). E-cadherin downregulation is postulated to liberate the catenin p120ctn from the plasma membrane and allow the translocation of p120ctn to the nucleus where it interacts with and inhibits the novel BTB/POZ transcription factor, Kaiso. Kaiso represses various tumourigenesis-associated genes via methylated CpG dinucleotides or a sequence-specific Kaiso binding site in their promoters. The p120ctn/Kaiso interaction has been detected in E-cadherin expressing cells of various origins, but the interaction has not been examined in cells that have undergone EMT. We hypothesize that p120ctn and Kaiso play a role in EMT by modulating the expression of EMT-associated genes. This study investigates, a) whether the interaction between p120ctn and Kaiso is affected by the induction of EMT and b) whether misexpression of p120ctn or Kaiso impacts EMT in cultured cells. To date, we have found that Transforming growth factor-β (hereafter TGF-β)-induced EMT results in increased p120ctn expression and decreased Kaiso expression. Moreover, in TGF-β treated cells, we detected a shift in the subcellular localization of p120ctn from the plasma membrane to the cytoplasm, whereas Kaiso remained predominantly nuclear. We also found that after EMT induction, the p120ctn/Kaiso interaction that is usually detected in normal epithelial cells was abolished. We are currently employing RNAi methodologies to test whether p120ctn or Kaiso depletion affects TGF-β-mediated EMT induction, and/or the expression of EMT-associated genes. These experiments will allow us to decipher the physiological relevance of the p120ctn/Kaiso interaction in EMT and tumourigenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA