ArticleiScience2026
E3 ubiquitin-ligase Hakai regulates LRP4 stability and Wnt/β-catenin signalling in colorectal cancer cells.
Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
The epithelial-mesenchymal transition is associated with the acquisition of cancer stem cell (CSC) traits that promote metastasis and therapy resistance. Here, we investigated the role of the E3 ubiquitin-ligase Hakai in regulating CSC-associated properties in colorectal cancer. Using tumoursphere models, loss-of-function approaches, proteomics, bioinformatics, and Wnt/β-catenin pathway studies, we found that Hakai depletion reduced tumoursphere formation, CSC marker expression, and Wnt target gene activation. Mechanistically, our findings support that Hakai regulates LRP4 stability, a negative regulator of Wnt signaling, consistent with ubiquitin-dependent mechanism. Consequently, Hakai enhances β-catenin/TCF transcriptional activity, nuclear accumulation of β-catenin, and attenuation of LRP4-mediated inhibition of Wnt signaling. Pharmacological inhibition of Hakai with Hakin-1, a selective inhibitor of its HYB domain responsible for E3 ubiquitin-ligase activity, reduced tumoursphere formation and promoted differentiation-associated features. Furthermore, these findings highlight Hakai inhibition as a potential CSC-directed therapeutic strategy in colorectal cancer.
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