CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR
CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR
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CSN6通过CHIP介导的EGFR降解控制胶质母细胞瘤的增殖和转移
DOI：
10.1038/onc.2016.280
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发表时间：
2017-02-23
期刊：
影响因子：
8
通讯作者：
Cui, H.
中科院分区：
文献类型：
--
作者：
Hou, J.;Deng, Q.;Cui, H.
CSN 6是组成型光形态发生9（COP 9）信号体（CSN）的关键亚基，其通过泛素-蛋白酶体系统作为癌症相关蛋白如p53、c-myc和c-Jun的降解的调节剂而受到关注，表明其在癌症发生中的重要性。然而，CSN 6在胶质母细胞瘤（GBM）中的生物学功能和分子机制仍然知之甚少。在这里，我们报告说，GBM肿瘤过表达CSN 6与正常脑组织相比，CSN 6促进GBM细胞增殖，迁移，侵袭和肿瘤发生。Erlotinib是一种小分子表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，用于揭示CSN 6对GBM细胞的增殖和转移作用是EGFR依赖性的。我们还发现，CSN 6通过降低EGFR泛素化水平来正向调节EGFR稳定性，从而提高EGFR的稳定表达。此外，这项研究首次描述了CSN 6相互作用的E3连接酶CHIP（热休克蛋白70相互作用蛋白的羧基末端）在癌细胞中调节EGFR泛素化的新作用。我们发现CSN 6与CHIP相关，并通过增加CHIP自身泛素化导致CHIP不稳定。此外，CSN 6降低肿瘤样品中CHIP表达并增加EGFR表达。该轴的失调促进GBM细胞的增殖和转移。因此，我们的研究提供了使用CSN 6-CHIP-EGFR轴作为癌症潜在治疗靶点的适用性的见解。
CSN6, a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), has received attention as a regulator of the degradation of cancer-related proteins such as p53, c-myc and c-Jun, through the ubiquitin-proteasome system, suggesting its importance in cancerogenesis. However, the biological functions and molecular mechanisms of CSN6 in glioblastoma (GBM) remain poorly understood. Here, we report that GBM tumors overexpressed CSN6 compared with normal brain tissues and that CSN6 promoted GBM cell proliferation, migration, invasion and tumorigenesis. Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was used to reveal that the proliferative and metastatic effects of CSN6 on GBM cells were EGFR dependent. We also found that CSN6 positively regulated EGFR stability via reduced levels of EGFR ubiquitination, thereby elevating steady expression of EGFR. In addition, this study is the first description of a novel role for the CSN6-interacting E3 ligase, CHIP (carboxyl terminus of heat-shock protein 70-interacting protein), regulating EGFR ubiquitination in cancer cells. We showed that CSN6 associated with CHIP and led to CHIP destabilization by increasing CHIP self-ubiquitination. Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples. Deregulation of this axis promoted GBM cell’s proliferation and metastasis. Thus, our study provides insights into the applicability of using the CSN6-CHIP-EGFR axis as a potential therapeutic target in cancer.