Wang Jiakun, He Aoxiao, Huang Zhihao, Lu Hongcheng, Xiong Jianghui, Wu Rongshou, Feng Qian, Ge Jin, Lei Jun, Li Enliang, Wu Linquan, Zhou Fan, Liao Wenjun
Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China.
Department of Emergency, The Second Affiliated Hospital, The Second Affiliated Hospital Jiangxi Medical College, Nanchang University, China.
Cell Signal. 2025 Oct;134:111953. doi: 10.1016/j.cellsig.2025.111953. Epub 2025 Jun 18.
Epithelial to mesenchymal transition (EMT) is known to play a critical role in tumor metastasis, and this is an obstacle for hepatocellular carcinoma (HCC) treatment. Here, we found that NCAPG, a non-SMC subunit in the concentrate I complex, was upregulated in tumor tissues in HCC patients and was correlated with a poor prognosis. We also found that NCAPG could promote EMT though restraining the ubiquitination of β-catenin in HCC in vitro and in vivo. Through Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays, we found that NCAPG might interact with SIP, which is the central component in the E3 ubiquitin ligase composed by Siah1-SIP-Skp1-Ebi. Mechanistically, NCAPG could weaken the stability of this E3 ubiquitin ligase though competitive binding with SIP，and this was the important factor for ubiquitination of β-catenin suppression. When NCAPG was upregulated, the stability of this E3 ubiquitin ligase declined because the interactions between Siah1/SIP and SIP/Skp1 were weakened. The opposite phenomenon occurred when NCAPG was downregulated. Furthermore, we discovered that the disordered domain of NCAPG (D-NCAPG) serves as the specific binding sites for SIP binding. In conclusion, this study reveals the underlying mechanism by which NCAPG promotes EMT in HCC, which may be useful in the treatment of NCAPG-expressing HCC.
上皮-间质转化（EMT）在肿瘤转移中起着关键作用，这是肝细胞癌（HCC）治疗的一个障碍。在此，我们发现浓缩物I复合物中的非SMC亚基NCAPG在HCC患者的肿瘤组织中上调，且与预后不良相关。我们还发现，NCAPG在体外和体内均可通过抑制HCC中β-连环蛋白的泛素化来促进EMT。通过免疫沉淀-质谱（IP-MS）和免疫共沉淀（Co-IP）分析，我们发现NCAPG可能与SIP相互作用，SIP是由Siah1-SIP-Skp1-Ebi组成的E3泛素连接酶的核心成分。从机制上讲，NCAPG可通过与SIP竞争性结合来削弱该E3泛素连接酶的稳定性，这是抑制β-连环蛋白泛素化的重要因素。当NCAPG上调时，由于Siah1/SIP与SIP/Skp1之间的相互作用减弱，该E3泛素连接酶的稳定性下降。当NCAPG下调时，情况则相反。此外，我们发现NCAPG的无序结构域（D-NCAPG）是SIP结合的特异性位点。总之，本研究揭示了NCAPG在HCC中促进EMT的潜在机制，这可能对治疗表达NCAPG的HCC有用。
