Erbin‐mediated Regulation of Colon Cancer

Abstract

The LAP (leucine‐rich repeat (LRR) and PDZ domain) family protein, ERBIN, is a basolateral‐localized scaffolding protein. Here, we have discovered that Erbin plays an important role in suppressing epithelial‐mesenchymal transition (EMT) of colorectal cancer (CRC) cells by controlling cell polarity as well as inhibiting CRC migration and metastasis. The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Increasing evidence has suggested that the disruption of this cellular polarity promotes the malignant progression of cancer cells. Here, we show that silencing Erbin results in the disruption of cell polarity in 3D cultures and mislocalization of EGF receptors in multiple CRC cell lines. As a consequence, activation of both Akt and ERK downstream of EGFR is enhanced as determined by Western blotting analysis. In addition to aberrant signaling, knockdown of Erbin induces an EMT‐like morphology and promotes migration in CRC cells, as observed using Transwell migration assays and live single‐cell microscopy. Similar to other LRR family members, the scaffolding function of Erbin could provide the required protein‐protein interactions to allow for spatial‐temporal control necessary to suppress oncogenic Akt and RAS/RAF signaling. Further supporting the role of Erbin as a tumor suppressor in CRC, the analysis of Erbin mRNA expression in two large sets of CRC patient samples revealed that Erbin is significantly downregulated in cancer specimens when compared to normal controls. Taken together, these data provide evidence for a novel role of Erbin in regulating colorectal cancer progression.