Esculetin suppresses tumor growth and metastasis by targeting Axin2/E-cadherin axis in colorectal cancer

Colorectal cancer (CRC) is the most common malignant disease worldwide due to its metastasis via the epithelial-mesenchymal transition (EMT) process. E-cadherin and Wnt signaling are emerging as potential targets for suppressing the EMT. In this context, Axin2 has been recognized as a negative regulator that inhibits glycogen synthase kinase 3β (GSK3β)-mediated degradation of Snail1, a transcriptional repressor of E-cadherin. However, Axin2 can also impede Wnt signaling via β-catenin degradation. Therefore, Axin2 may serve as either a promoter or suppressor of tumors, and the effects of its inhibition on the cell proliferation and metastasis of CRC require further elucidation. Here, esculetin (ES), a coumarin, was found to have the most potential effects on both β-catenin-responsive transcriptional and E-cadherin promoter activities. ES also showed anti-proliferative and anti-invasive activities in CRC cells. Mechanistically, Axin2 suppression by ES contributed to E-cadherin-mediated Wnt signaling inhibition. Moreover, the ability of ES to inhibit tumor growth and metastasis via Axin2 suppression was further supported in an HCT116-implanted orthotopic mouse model. Collectively, these findings suggest that targeting the Axin2/E-cadherin axis by ES may be an attractive therapeutic strategy for the treatment of metastatic CRC.