COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL
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Kensuke Watanabe1, Satoru Yokoyama1, Naoki Kaneto1, Takashi Hori2, Yusuke Iwakami1, Shinichiro Kato1, Yoshihiro Hayakawa1, Hiroaki Sakurai1,3, Junya Fukuoka4 and Ikuo Saiki1
1Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
2Department of Diagnostic Pathology, Toyama University Hospital, Toyama 930-0194, Japan
3Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
4Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
Satoru Yokoyama, email: [email protected]
Keywords: SNAIL; metastasis; COPS5; deubiquitination; lung cancer
Received: April 07, 2017 Accepted: March 21, 2018 Published: April 17, 2018
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.
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