ABLIM1, a novel ubiquitin E3 ligase, promotes growth and metastasis of colorectal cancer through targeting IĸBα ubiquitination and activating NF-ĸB signaling
ABLIM1, a novel ubiquitin E3 ligase, promotes growth and metastasis of colorectal cancer through targeting IĸBα ubiquitination and activating NF-ĸB signaling
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DOI：
10.1038/s41418-024-01256-y
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发表时间：
2024-01-16
影响因子：
12.4
通讯作者：
Yao，Linhua
中科院分区：
文献类型：
--
作者：
He，Ying;Shi，Qian;Yao，Linhua
肌动蛋白结合LIM蛋白1（ABLIM 1）是LIM结构域蛋白家族的一员，已被报道为多种肿瘤的抑制因子，而其在结直肠癌（CRC）中的作用尚不清楚。在这项研究中，我们发现ABLIM 1在结直肠癌患者中上调，高水平的ABLIM 1预示着短的无病生存时间。慢病毒敲低CRC细胞系中的ABLIM 1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变的生长受损，而ABLIM 1过表达加速体外肿瘤生长和侵袭。从机制上讲，我们发现ABLIM 1通过调节IAPB α泛素化和蛋白酶体介导的降解来激活NF-κ B/CCL-20信号传导。进一步的免疫共沉淀、体内和体外泛素化实验表明ABLIM 1是一种新的泛素E3连接酶，可与I β B α结合。有趣的是，ABLIM 1的E3连接酶催化活性依赖于它的402- 778 aa而不是它的LIM结构域，它与IAPB α的相互作用依赖于HP结构域。我们的研究结果描述了ABLIM 1在CRC进展中的致癌作用，并揭示了它作为一种新型的靶向IFN-γ B α的E3连接酶，为肿瘤中NF-κ B信号转导的调控提供了新的见解。
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.