Authors
Andrea Rodríguez-Alonso, Lía Jove, Gloria Alfonsín, Marta Tasende, Ingrid Jordens, Madelon Maurice, Angélica Figueroa
Published in
iScience. Volume 29. Issue 8. Pages 116743. Aug 21, 2026. Epub Jul 10, 2026.
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.
PMID:
42472112
Bibliographic data and abstract were imported from PubMed on 19 Jul 2026.
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