Department of Gastroenterology, The First Hospital of Jilin University, Changchun, 130021, China.
Department of Endocrinology, The First Hospital of Jilin University, Changchun, 130021, China.
Biochem Biophys Res Commun. 2018 Nov 30;506(3):698-702. doi: 10.1016/j.bbrc.2018.10.130. Epub 2018 Oct 27.
In addition to the involvement in white matter lesion, tripartite-motif protein family member 65 (TRIM65) has also been implicated in tumorigenesis as a potential oncogene. However, the underlining mechanisms of TRIM65 functions and its clinical implication still remain to be further elucidated. In the present study, we found that TRIM65 binds to the N-terminus of p53 tumor suppressor and thus competes with MDM2 for p53 binding. Intriguingly, analysis of the Cancer Genome Atlas (TCGA) gene alteration database revealed that elevated expression of TRIM65 is mutually exclusive to MDM2 up-regulation in human lung adenocarcinoma patients, indicating potential compensatory effect of one over the other. Indeed, overexpression of TRIM65 renders lung cancer cell line resistance to Nutlin-3a, an effective MDM2 inhibitor, as determined by p53 activation and cell proliferation assays. Furthermore, depletion of TRIM65 using siRNA in combination with Nutlin-3a treatment demonstrates enhanced anti-tumor effects on lung cancer cell line. Collectively, our findings provide the rationale for developing strategies to target TRIM65 for lung cancer intervention, potentially in combination with MDM2 inhibition.
除了参与白质病变外，三结构域蛋白家族成员 65（TRIM65）也被牵连到肿瘤发生中，作为一种潜在的癌基因。然而，TRIM65 的功能的潜在机制及其临床意义仍有待进一步阐明。在本研究中，我们发现 TRIM65 与抑癌基因 p53 的 N 端结合，从而与 MDM2 竞争与 p53 的结合。有趣的是，对癌症基因组图谱（TCGA）基因改变数据库的分析显示，在人类肺腺癌患者中，TRIM65 的高表达与 MDM2 的上调相互排斥，表明两者存在潜在的代偿效应。事实上，TRIM65 的过表达使肺癌细胞系对 Nutlin-3a（一种有效的 MDM2 抑制剂）产生耐药性，这通过 p53 激活和细胞增殖测定来确定。此外，用 siRNA 耗尽 TRIM65 并与 Nutlin-3a 联合治疗，显示出对肺癌细胞系更强的抗肿瘤作用。总之，我们的研究结果为开发针对 TRIM65 的肺癌干预策略提供了依据，可能与 MDM2 抑制联合使用。
