Epsin is required for Dishevelled stability and Wnt signaling activation in colon cancer development

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.