CYLD destabilizes NoxO1 protein by promoting ubiquitination and regulates prostate cancer progression

被引:22
|
作者
Haq, Saba [1 ]
Sarodaya, Neha [2 ]
Karapurkar, Janardhan Keshav [2 ]
Suresh, Bharathi [2 ]
Jo, Jung Ki [3 ]
Singh, Vijai [4 ]
Bae, Yun Soo [5 ]
Kim, Kye-Seong [2 ,6 ]
Ramakrishna, Suresh [2 ,6 ]
机构
[1] Hanyang Univ, Dept Life Sci, Coll Nat Sci, Seoul 04763, South Korea
[2] Hanyang Univ, Grad Sch Biomed Sci & Engn, Seoul 04763, South Korea
[3] Hanyang Univ, Dept Urol, Coll Med, Seoul 04763, South Korea
[4] Indrashil Univ, Sch Sci, Dept Biosci, Mehsana, Gujarat, India
[5] Ewha Womans Univ, Dept Life Sci, Seoul, South Korea
[6] Hanyang Univ, Coll Med, Seoul 04763, South Korea
基金
新加坡国家研究基金会;
关键词
Proteolysis; CRISPR; Cas9; ROS; Proteasomal degradation; Deubiquitination; Colon cancer; TUMOR-SUPPRESSOR; NADPH OXIDASES; SUBCELLULAR-LOCALIZATION; DEUBIQUITINATING ENZYME; HUMAN-CELLS; ROS; COLON; ACTIVATION; PROLIFERATION; EXPRESSION;
D O I
10.1016/j.canlet.2021.10.032
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The NADPH oxidase (Nox) family of enzymes is solely dedicated in the generation of reactive oxygen species (ROS). ROS generated by Nox are involved in multiple signaling cascades and a myriad of pathophysiological conditions including cancer. As such, ROS seem to have both detrimental and beneficial roles in a number of cellular functions, including cell signaling, growth, apoptosis and proliferation. Regulatory mechanisms are required to control the activity of Nox enzymes in order to maintain ROS balance within the cell. Here, we performed genome-wide screening for deubiquitinating enzymes (DUBs) regulating Nox organizer 1 (NoxO1) protein expression using a CRISPR/Cas9-mediated DUB-knockout library. We identified cylindromatosis (CYLD) as a binding partner regulating NoxO1 protein expression. We demonstrated that the overexpression of CYLD promotes ubiquitination of NoxO1 protein and reduces the NoxO1 protein half-life. The destabilization of NoxO1 protein by CYLD suppressed excessive ROS generation. Additionally, CRISPR/Cas9-mediated knockout of CYLD in PC-3 cells promoted cell proliferation, migration, colony formation and invasion in vitro. In xenografted mice, injection of CYLD-depleted cells consistently led to tumor development with increased weight and volume. Taken together, these results indicate that CYLD acts as a destabilizer of NoxO1 protein and could be a potential tumor suppressor target for cancer therapeutics.
引用
收藏
页码:146 / 157
页数:12
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