Abstract
Uncontrolled canonical Wnt signaling supports colon epithelial tumor expansion and malignant transformation. Understanding the regulatory mechanisms involved is crucial for elucidating the pathogenesis of and will provide new therapeutic targets for colon cancer. Epsins are ubiquitin-binding adaptor proteins upregulated in several human cancers; however, epsins’ involvement in colon cancer is unknown. Here we show that loss of intestinal epithelial epsins protects against colon cancer by significantly reducing the stability of the crucial Wnt signaling effector, dishevelled (Dvl2), and impairing Wnt signaling. Consistently, epsins and Dvl2 are correspondingly upregulated in colon cancer. Mechanistically, epsin binds Dvl2 via its epsin N-terminal homology domain and ubiquitin-interacting motifs and prohibits Dvl2 polyubiquitination and degradation. Our findings reveal an unconventional role for epsins in stabilizing Dvl2 and potentiating Wnt signaling in colon cancer cells to ensure robust colon cancer progression. Epsins’ pro-carcinogenic role suggests they are potential therapeutic targets to combat colon cancer.
Highlights
Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation
Given that both the Wnt receptors and Dvl are upregulated in cancer and result in elevated canonical Wnt signalling, it has been hypothesized that alterations in the stabilization and/or internalization of the Fzd:LRP:Dvl complex may contribute to the aberrant canonical Wnt signalling linked to colon cancer development[25,26,27]
Using an Oncomine database from The National Cancer Institute Cancer Genome Atlas containing publically available cDNA microarray data, we found that the gene expression of epsin 1 and epsin 2 was significantly upregulated in human colon cancer (Fig. 1a,b)
Summary
Uncontrolled canonical Wnt signalling supports colon epithelial tumour expansion and malignant transformation. Dvl is recruited to the heterodimeric Wnt receptor complex, consisting of a single Fzd and LRP, in response to ligand stimulation and plays a crucial role in mediating Axin/GSK3/APC destruction complex disassembly[23,24] Given that both the Wnt receptors and Dvl are upregulated in cancer and result in elevated canonical Wnt signalling, it has been hypothesized that alterations in the stabilization and/or internalization of the Fzd:LRP:Dvl complex may contribute to the aberrant canonical Wnt signalling linked to colon cancer development[25,26,27]. We investigate the potential role that epsins play in regulating colon cancer development using a unique colon cancer mouse model with inducible intestinal epithelial cell (IEpC)-specific epsin deficiency. Because Dvl[2] is reportedly upregulated in and contributes to cancer progression[19,21,22], we propose a model in which epsin upregulation during the early stages of tumorigenesis promotes Dvl[2] stabilization, deregulates canonical Wnt signalling and facilitates colon cancer development[21,22]
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