Oncotarget

Research Papers:

COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL

Kensuke Watanabe, Satoru Yokoyama _, Naoki Kaneto, Takashi Hori, Yusuke Iwakami, Shinichiro Kato, Yoshihiro Hayakawa, Hiroaki Sakurai, Junya Fukuoka and Ikuo Saiki

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Oncotarget. 2018; 9:20670-20680. https://doi.org/10.18632/oncotarget.25060

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Abstract

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

Correspondence to:

Satoru Yokoyama, email: yokoyama@inm.u-toyama.ac.jp

Keywords: SNAIL; metastasis; COPS5; deubiquitination; lung cancer

Received: April 07, 2017     Accepted: March 21, 2018     Published: April 17, 2018

ABSTRACT

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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