Pals1 functions as a tumor suppressor regulating cell polarity, Hippo signaling and cancer progression

Epithelial cell polarity is of vital importance for the organization and function of epithelial tissues and is primarily maintained by three protein complexes, the Crumbs complex, the Par complex and the Scribble complex. Most of the polarity proteins within these complexes are highly conserved and play pivotal roles in embryonic development, cell-cell adhesion and cell migration. Recent studies have demonstrated that deregulation of epithelial polarity is a hallmark of tumor progression, in particular during the metastatic process. This study was conducted to examine the role of the tight junction protein Pals1 in the maintenance of cell polarity, and cancer. RNA interference and CRISPR/Cas9 gene deletion approaches were used to downregulate or deplete Pals1 in MDCKII, HCT116 and DLD1 cell lines. Reduction in Pals1 resulted in atypical expression levels of polarity proteins and defects in Hippo pathway regulation. Moreover, Pals1 loss caused E-cadherin reduction and enhanced cell migration. Pals1 deficient cells exhibited typical markers, inferring epithelial-to-mesenchymal transition. Further in vivo xenograft experiments revealed a function of Pals1 in cancer progression, as tumors derived from Pals1-deficient cells showed increased growth and more extensive liver and lung metastases. Taken together, these findings support a close link between epithelial cell polarity and tumorigenesis, and suggest the existence of a novel Pals1-mediated mechanism of tumor suppression. Thus, the pathophysiological consequences of Pals1 alteration must be investigated further, and used to develop new therapeutic strategies against this devastating disease