Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the β‐catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε 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 CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/β‐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 CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/β‐catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.

中文翻译：

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CK1ε/SIAH1轴调节结直肠癌细胞中AXIN1的稳定性

酪蛋白激酶 1ε (CK1ε) 和轴抑制剂 1 (AXIN1) 是经典 Wnt 信号传导中 β-连环蛋白破坏复合物的重要组成部分。CK1ε已被证明与AXIN1相互作用，但其生理功能和在肿瘤发生中的作用仍不清楚。在这项研究中，我们发现CK1δ/ε抑制剂通过靶向CK1ε显着提高结直肠癌（CRC）细胞中AXIN1蛋白水平。从机制上讲，CK1ε通过促进E3泛素蛋白连接酶SIAH1与AXIN1的相互作用，通过泛素-蛋白酶体途径促进AXIN1降解。CK1ε 的遗传或药理学抑制以及 CK1ε 的敲低SIAH1下调Wnt/β-catenin依赖基因的表达，抑制CRC细胞的活力，抑制CRC的肿瘤发生和进展体外和体内。总之，我们的结果表明CK1ε通过调节AXIN1的稳定性在CRC的发生和进展中发挥致癌作用。这些发现揭示了 CK1ε 调节 Wnt/β-catenin 信号通路的新机制，并强调了靶向 CK1ε/SIAH1 轴在 CRC 中的治疗潜力。