Actin-binding LIM protein 1 (ABLIM1), a member of the LIM-domain protein family, has been reported as a suppressor in several tumors whereas its role in colorectal cancer (CRC) remains unknown. In this study, we find that ABLIM1 is up-regulated in CRC patients and high levels of ABLIM1 predict short disease-free survival time. Knock-down of ABLIM1 in CRC cell lines by lenti-virus leads to inhibited cell proliferation, migration, and invasion capabilities in vitro and impaired growth of tumor xenografts and liver metastasis lesions in vivo, while ABLIM1 overexpression accelerates tumor growth and invasion in vitro. Mechanistically, we uncover that ABLIM1 activates the NF-ĸB/CCL-20 signaling through modulating IĸBα ubiquitination and proteasomal-mediated degradation. Further co-immunoprecipitation, in vivo and in vitro ubiquitination assays reveal ABLIM1 as a novel ubiquitin E3 ligase binding to IĸBα. Interestingly, The E3 ligase catalysis activity of ABLIM1 depends on its 402–778aa rather than its LIM domains and its interaction with IĸBα relies on the HP domain. Our findings delineate the oncogenic role of ABLIM1 in CRC progression and reveal it as a novel E3 ligase targeting IĸBα, providing new insights into the regulation of NF-ĸB signaling in tumors.

肌动蛋白结合 LIM 蛋白 1 (ABLIM1) 是 LIM 结构域蛋白家族的成员，已被报道为多种肿瘤的抑制因子，但其在结直肠癌 (CRC) 中的作用仍不清楚。在这项研究中，我们发现 ABLIM1 在 CRC 患者中表达上调，高水平的 ABLIM1 预示着较短的无病生存时间。慢病毒敲低CRC细胞系中的ABLIM1会导致体外细胞增殖、迁移和侵袭能力受到抑制，体内肿瘤异种移植物和肝转移病灶的生长受损，而ABLIM1过表达会加速体外肿瘤的生长和侵袭。从机制上讲，我们发现 ABLIM1 通过调节 IĸBα 泛素化和蛋白酶体介导的降解来激活 NF-ĸB/CCL-20 信号传导。进一步的免疫共沉淀、体内和体外泛素化测定表明 ABLIM1 是一种与 IĸBα 结合的新型泛素 E3 连接酶。有趣的是，ABLIM1 的 E3 连接酶催化活性取决于其 402-778aa 而不是其 LIM 结构域，并且其与 IĸBα 的相互作用依赖于 HP 结构域。我们的研究结果描述了 ABLIM1 在 CRC 进展中的致癌作用，并揭示了它是一种靶向 IĸBα 的新型 E3 连接酶，为肿瘤中 NF-ĸB 信号传导的调节提供了新的见解。