circGIGYF1 inhibits stemness and metastasis in colorectal cancer by promoting WWP2-HOXD13 interaction to regulate β-catenin signalling.

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, with cancer stemness and metastasis being critical factors contributing to poor prognosis. While circular RNAs are emerging as important regulators in cancer progression, the role of circGIGYF1 in CRC development is poorly understood. Here, we found that downregulated circGIGYF1 is linked to poor survival rate in CRC patients. circGIGYF1 inhibits CRC stemness, epithelial-mesenchymal transition, and metastatic potential both in vitro and in vivo. Mechanistically, circGIGYF1 promotes the interaction between WWP2 and HOXD13, enhancing HOXD13 ubiquitination and subsequent degradation. This degradation prevented HOXD13 from binding to the CTNNB1 promoter, thereby suppressing Wnt/β-catenin signalling pathway activation. Importantly, circGIGYF1 overexpression or HOXD13 knockdown significantly reduces tumor growth and liver metastasis in mouse models. These findings reveal a circGIGYF1/WWP2/HOXD13/β-catenin regulatory axis in CRC progression and highlight circGIGYF1 as a potential therapeutic target for developing strategies to combat CRC metastasis and recurrence.