Abstract
The canonical Wnt signaling pathway is crucial for embryonic development and adult tissue homeostasis. Activating mutations in the Wnt pathway are frequently associated with the pathogenesis of various types of cancer, particularly colon cancer. Upon Wnt stimulation, β-catenin plays a central role as a coactivator through direct interaction with Tcf/Lef transcription factors to stimulate target gene expression. We have previously shown that the evolutionarily conserved protein Chibby (Cby) physically binds to β-catenin to repress β-catenin-dependent gene activation by 1) competing with Tcf/Lef factors for binding to β-catenin and 2) facilitating nuclear export of β-catenin via interaction with 14-3-3 proteins. In this study, we employed human colon adenocarcinoma SW480 cells with high levels of endogenous β-catenin to address a potential tumor suppressor role of Cby. In SW480 stable cells expressing wild-type Cby (CbyWT), but not 14-3-3-binding- defective Cby mutant CbyS20A, a significant fraction of endogenous β-catenin was detected in the cytoplasm. Consistent with this, CbyWT-expressing cells showed low levels of β-catenin signaling activity, leading to reduced growth. Our results suggest that Cby, in collaboration with 14-3-3 proteins, can counteract oncogenic β-catenin signaling in colon cancer cells.
Highlights
The canonical Wnt/β-catenin signaling pathway is highly conserved throughout evolution and plays diverse roles in embryonic development and adult homeostasis by regulating cell proliferation, cell fate decisions, as well as stem cell maintenance and self-renewal [1,2,3,4]. β-Catenin serves as a key transcriptional coactivator for transducing canonical Wnt signals from the cell surface to the nucleus
It is well established that the canonical Wnt/β-catenin signaling pathway is aberrantly activated in most colon cancers
It has been established that the canonical Wnt/β-catenin signaling pathway is aberrantly activated in the vast majority of colon cancers and to a lesser extent in other tumor types
Summary
The canonical Wnt/β-catenin signaling pathway is highly conserved throughout evolution and plays diverse roles in embryonic development and adult homeostasis by regulating cell proliferation, cell fate decisions, as well as stem cell maintenance and self-renewal [1,2,3,4]. β-Catenin serves as a key transcriptional coactivator for transducing canonical Wnt signals from the cell surface to the nucleus. In the absence of Wnt ligands, cytoplasmic β-catenin becomes sequentially phosphorylated by casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3) in the so-called “destruction complex” containing the tumor suppressors Axin and APC, and targeted for ubiquitin-mediated proteasomal degradation [2,3,5]. Greater than 70% of colon cancers exhibit elevated Wnt/ β-catenin signaling activity. Mutations in APC or Axin compromise their function within the β-catenin destruction complex, whereas oncogenic mutations in the Nterminal phosphorylation domain of β-catenin block its degradation via the ubiquitin-proteasome pathway. The Wnt/β-catenin pathway has gained recognition as an enticing molecular target for therapeutics of human cancers [7,11,12]
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