The CK1ε/SIAH1 axis regulates AXIN1 stability in colorectal cancer cells

Casein kinase 1 epsilon (CK1 epsilon) and axis inhibitor 1 (AXIN1) are crucial components of the beta-catenin destruction complex in canonical Wnt signaling. CK1 epsilon has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1 delta/epsilon inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1 epsilon. Mechanistically, CK1 epsilon promoted AXIN1 degradation by the ubiquitin-proteasome pathway by promoting the interaction of E3 ubiquitin-protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1 epsilon and knockdown of SIAH1 downregulated the expression of Wnt/beta-catenin-dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1 epsilon exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1 epsilon regulates the Wnt/beta-catenin signaling pathway and highlight the therapeutic potential of targeting the CK1 epsilon/SIAH1 axis in CRC.