COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL.
COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL.
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DOI：
10.18632/oncotarget.25060
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发表时间：
2018-04-17
期刊：
影响因子：
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通讯作者：
Saiki I
中科院分区：
文献类型：
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作者：
Watanabe K;Yokoyama S;Kaneto N;Hori T;Iwakami Y;Kato S;Hayakawa Y;Sakurai H;Fukuoka J;Saiki I
癌症转移是癌症患者死亡的主要原因。转录因子SNAIL在癌症转移和进展中发挥着重要作用，其表达受到泛素-蛋白酶体系统通过泛素连接酶和去泛素化酶之间的平衡的严格调控。虽然 SNAIL 的几种泛素连接酶已被鉴定，但去泛素化酶尚不清楚。在本研究中，我们通过使用 siRNA 文库筛选，将 COP9 信号体亚基 5 (COPS5) 鉴定为 SNAIL 的去泛素化酶。 COPS5 下调显着降低了 SNAIL 的表达，并损害了肺癌细胞的体外和体内转移潜力。重要的是，我们证明了 COPS5 与 SNAIL 结合并通过去泛素化稳定其表达。此外，我们通过组织微阵列分析观察肺腺癌临床组织样本中COPS5和SNAIL表达之间的正相关性。这些发现提供了强有力的证据，表明COPS5作为SNAIL的去泛素化酶可以成为癌症转移的新治疗靶点。
Cancer metastasis is a major cause of mortality in cancer patients. The transcription factor SNAIL plays an important role in cancer metastasis and progression, and its expression is tightly regulated by the ubiquitin-proteasome system through the balance between ubiquitin ligases and deubiquitinating enzymes. While several ubiquitin ligases of SNAIL have been identified, it is not yet clear regarding deubiquitinating enzyme. In this study, we identified COP9 signalosome subunit 5 (COPS5) as a deubiquitinating enzyme of SNAIL by using siRNA library screening. COPS5 downregulation significantly reduced the expression of SNAIL and impaired the metastatic potential of lung cancer cells both in vitro and in vivo. Importantly, we demonstrated that COPS5 binds to SNAIL and stabilizes its expression by deubiquitination. Furthermore, we observed the positive correlation between COPS5 and SNAIL expression in the clinical tissue samples of lung adenocarcinomas by using tissue microarray analysis. These findings provide strong evidence that COPS5 can be a new therapeutic target for cancer metastasis as a deubiquitinating enzyme of SNAIL.