Wei Chi-Hsuan, Weng Chia-Wei, Wu Chih-Ying, Chen Hsuan-Yu, Chang Ya-Hsuan, Chang Gee-Chen, Chen Jeremy J W
Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Cell Death Dis. 2025 Feb 11;16(1):88. doi: 10.1038/s41419-025-07421-6.
Ubiquitination is a posttranslational modification that regulates tumour progression-associated proteins through the ubiquitin‒proteasome system, making E3 ligases potential antitumour targets. Here, we report that TRIM8, a member of the TRIM family and an E3 ligase, can act as a tumour suppressor in non-small cell lung cancer (NSCLC). Both gain- and loss-of-function experiments revealed that TRIM8 inhibits the proliferation, colony formation, migration and invasion of NSCLC cells. Experiments with a xenograft model showed that TRIM8 expression suppresses tumour metastasis in vivo. Moreover, low expression of TRIM8 was associated with poor overall survival in both the Taiwanese and GEO lung cancer cohorts. TRIM8 overexpression in lung cancer cells reduced MYOF expression, and restoring MYOF rescued cell migration in TRIM8-overexpressing cells. TRIM8 targeted MYOF for K48-linked ubiquitination, facilitating proteasome-mediated degradation and subsequently suppressing the extracellular secretion of MMPs. Our results provide new insights into the contribution of TRIM8 to lung cancer progression, suggesting that TRIM8 is a new biomarker and a novel therapeutic target for lung cancer.
泛素化是一种翻译后修饰，通过泛素-蛋白酶体系统调节与肿瘤进展相关的蛋白质，使E3连接酶成为潜在的抗肿瘤靶点。在此，我们报告TRIM8是TRIM家族的成员之一，也是一种E3连接酶，在非小细胞肺癌（NSCLC）中可作为肿瘤抑制因子。功能获得和功能缺失实验均表明，TRIM8抑制NSCLC细胞的增殖、集落形成、迁移和侵袭。异种移植模型实验表明，TRIM8表达可抑制体内肿瘤转移。此外，在台湾和GEO肺癌队列中，TRIM8低表达均与总体生存率低相关。肺癌细胞中TRIM8过表达降低了MYOF表达，而恢复MYOF表达可挽救TRIM8过表达细胞中的细胞迁移。TRIM8靶向MYOF进行K48连接的泛素化，促进蛋白酶体介导的降解，随后抑制MMPs的细胞外分泌。我们的结果为TRIM8对肺癌进展的作用提供了新的见解，表明TRIM8是肺癌的一种新的生物标志物和新型治疗靶点。
