Dual Role of Chibby in Regulation of Cell Growth and Mesenchymal-to-Epithelial Transition-like Processes

Abstract

The Wnt/beta-catenin signaling pathway is well known for its prominent role in tumorigenesis of colon cancers, but also of some other tumors. Beta-Catenin, the downstream mediator of canonical Wnt-signaling, is continuously degraded in the absence of Wnt signaling but stabilized upon activation of the pathway. Beta-Catenin then activates transcription of target genes in the nucleus, leading e.g. to proliferation, invasiveness and anoikis resistance, and can induce epithelial-to-mesenchymal transition (EMT). Apart from its function as a transcriptional coactivator, beta-catenin forms part of adherens junctions where it plays a pivotal role mediating the connection between the adherens junction protein E-cadherin and the actin cytoskeleton, and its loss from the membrane entrails reduced cell-cell adhesion. This role contrasts beta-catenin's function in the nucleus since formation of E-cadherin-mediated adherens junctions reverses a malignant phenotype, effectuating mesenchymal-to-epithelial transition (MET), in a variety of tumor cell lines. The small, evolutionarily conserved protein Chibby was initially discovered as beta-catenin binding partner. Our lab has shown that Chibby shuttles beta-catenin out of the nucleus, in cooperation with 14-3-3 proteins. By this mechanism and by competing with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors for beta-catenin binding, Chibby inhibits nuclear beta-catenin signaling. We show here that Chibby counteracts both of beta-catenin's opposing roles in that a) Chibby can reduce beta-catenin nuclear signaling and cell proliferation in human colon cancer cells bearing stabilized beta-catenin by reducing nuclear levels of beta-catenin, and that b) Chibby knock-down leads to increased proteins levels of E-cadherin and beta-catenin at the plasma membrane, to the point of inducing mesenchymal-to-epithelial reversion with reduced tumor characteristics in human embryonic kidney and human colon cancer cells, and that this is due at least in part to increased transcription of the E-cadherin gene. These findings are relevant to further development of treatment options for Wnt/beta-catenin-dependent tumors.