Li Yang, Ma Chengyuan, Zhou Tong, Liu Ying, Sun Luyao, Yu Zhenxiang
Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China.
Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China.
Biochem Biophys Res Commun. 2016 Apr 22;473(1):278-282. doi: 10.1016/j.bbrc.2016.03.093. Epub 2016 Mar 21.
Tripartite-motif protein family member 65 (TRIM65) is an important protein involved in white matter lesion. However, the role of TRIM65 in human cancer remains less understood. Through the Cancer Genome Atlas (TCGA) gene alteration database, we found that TRIM65 is upregulated in a significant portion of non-small cell lung carcinoma (NSCLC) patients. Our cell growth assay revealed that TRIM65 overexpression promotes cell proliferation, while knockdown of TRIM65 displays opposite effect. Mechanistically, TRIM65 binds to p53, one of the most critical tumor suppressors, and serves as an E3 ligase toward p53. Consequently, TRIM65 inactivates p53 through facilitating p53 poly-ubiquitination and proteasome-mediated degradation. Notably, chemotherapeutic reagent cisplatin induction of p53 is markedly attenuated in response to ectopic expression of TRIM65. Cell growth inhibition by TRIM65 knockdown is more significant in p53 positive H460 than p53 negative H1299 cells, and knockdown of p53 in H460 cells also shows compromised cell growth inhibition by TRIM65 knockdown, indicating that p53 is required, at least in part, for TRIM65 function. Our findings demonstrate TRIM65 as a potential oncogenic protein, highly likely through p53 inactivation, and provide insight into development of novel approaches targeting TRIM65 for NSCLC treatment, and also overcoming chemotherapy resistance.
三联基序蛋白家族成员65（TRIM65）是一种参与白质病变的重要蛋白质。然而，TRIM65在人类癌症中的作用仍鲜为人知。通过癌症基因组图谱（TCGA）基因改变数据库，我们发现TRIM65在相当一部分非小细胞肺癌（NSCLC）患者中上调。我们的细胞生长试验表明，TRIM65的过表达促进细胞增殖，而敲低TRIM65则显示出相反的效果。从机制上讲，TRIM65与最关键的肿瘤抑制因子之一p53结合，并作为p53的E3连接酶。因此，TRIM65通过促进p53多聚泛素化和蛋白酶体介导的降解使p53失活。值得注意的是，在TRIM65异位表达的情况下，化疗药物顺铂对p53的诱导作用明显减弱。在p53阳性的H460细胞中，敲低TRIM65对细胞生长的抑制作用比p53阴性的H1299细胞更显著，并且在H460细胞中敲低p53也显示出敲低TRIM65对细胞生长抑制作用的减弱，这表明p53至少部分是TRIM65发挥功能所必需的。我们的研究结果表明TRIM65是一种潜在的致癌蛋白，很可能是通过使p53失活，并为开发针对TRIM65的非小细胞肺癌治疗新方法以及克服化疗耐药性提供了思路。
