Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, 250012, Jinan, PR China.
Shandong Key Laboratory of Brain Function Remodeling, 250012, Jinan, PR China.
Oncogene. 2019 Sep;38(37):6414-6428. doi: 10.1038/s41388-019-0888-1. Epub 2019 Jul 22.
Increasing evidence demonstrates that ubiquitin specific protease 39 (USP39) plays an oncogenic role in various human tumors. Here, using expression analysis of the publicly available Oncomine database, clinical glioma patient samples, and glioma cells, we found that USP39 was overexpressed in human gliomas. Knockdown of USP39 in glioma cells demonstrated that the protein promoted cell growth, invasion and migration in vitro and in a tumor model in nude mice. To identify mediators of USP39 growth-promoting properties, we used luciferase reporter constructs under transcriptional control of various promoters specific to seven canonical cancer-associated pathways. Luciferase activity from a synthetic TEAD-dependent YAP/TAZ-responsive reporter, as a direct readout of the Hippo signaling pathway, was decreased by 92% in cells with USP39 knockdown, whereas the luciferase activities from the other six cancer pathways, including MAPK/ERK, MAPK/JNK, NFκB, Notch, TGFβ, and Wnt, remained unchanged. TAZ protein expression however was decreased independent of canonical Hippo signaling. Immunohistochemistry revealed a positive correlation between USP39 and TAZ proteins in orthotopic xenografts derived from modified glioma cells expressing USP39 shRNAs and primary human glioma samples (p < 0.05). Finally, loss of USP39 decreased TAZ pre-mRNA splicing efficiency in glioma cells in vitro, which led to reduced levels of TAZ protein. In summary, USP39 has oncogenic properties that increase TAZ protein levels by inducing maturation of its mRNA. USP39 therefore provides a novel therapeutic target for the treatment of human glioma.
越来越多的证据表明，泛素特异性蛋白酶 39（USP39）在各种人类肿瘤中发挥致癌作用。在这里，我们使用公开的 Oncomine 数据库、临床脑胶质瘤患者样本和脑胶质瘤细胞的表达分析，发现 USP39 在人脑胶质瘤中过表达。在脑胶质瘤细胞中敲低 USP39 表明，该蛋白在体外和裸鼠肿瘤模型中促进细胞生长、侵袭和迁移。为了确定 USP39 促进生长特性的介质，我们使用了受七种经典癌症相关途径的特定启动子转录控制的荧光素酶报告构建体。荧光素酶活性从合成的 TEAD 依赖性 YAP/TAZ 反应性报告器中降低了 92%，而来自其他六个癌症途径（包括 MAPK/ERK、MAPK/JNK、NFκB、Notch、TGFβ和 Wnt）的荧光素酶活性保持不变。然而，TAZ 蛋白表达独立于经典 Hippo 信号。免疫组织化学显示，在表达 USP39 shRNA 的改良脑胶质瘤细胞来源的原位异种移植和原发性人脑胶质瘤样本中，USP39 和 TAZ 蛋白之间存在正相关（p < 0.05）。最后，USP39 的缺失降低了体外脑胶质瘤细胞中 TAZ 前体 mRNA 的剪接效率，导致 TAZ 蛋白水平降低。总之，USP39 具有致癌特性，通过诱导其 mRNA 的成熟来增加 TAZ 蛋白水平。因此，USP39 为治疗人类脑胶质瘤提供了一个新的治疗靶点。
