Year-end Sale % OFF 
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.
Highlights
The critical characteristics of cancers are the ability to invade surrounding tissues and metastasize to distal tissues, which is the major cause of mortality in cancer patients [1]
The effects of PR-619 on the invasiveness were stronger than that on the cell growth (Supplementary Figure 1). These results indicate that deubiquitinating enzymes (DUBs) regulate SNAIL degradation and cancer cell invasiveness
To investigate the significance of SNAIL deubiquitination by COP9 signalosome subunit 5 (COPS5) in cancer metastasis, we introduced the mutant forms of SNAIL protein (K98R/ K137R/K146R, referred to as SNAIL-3KR) in A549 cells, Figure 1: Inhibition of deubiquitinating enzymes suppressed cancer cell invasion. (A) A549 or Panc-1 cells were treated with 50 μg/ml cycloheximide (CHX) for the indicated times and subjected to Western blotting
Summary
The critical characteristics of cancers are the ability to invade surrounding tissues and metastasize to distal tissues, which is the major cause of mortality in cancer patients [1]. The migration ability or invasiveness of cancer cells plays a critical role during metastasis. SNAIL is a transcription factor that regulates the migration ability in some cancer types, including lung and pancreas [3]. Recent studies suggest that SNAIL has a much broader impact on cancer progression such as the induction of epithelial-to-mesenchymal transition [3], an enhancement of recruitment of macrophages [4], an induction of tumor-initiating properties [5], a suppression of host immune surveillance [6], drug resistance [7], and cancer metabolism [8]. Given that SNAIL has multiple functions in cancer progression, it is important to understand the regulatory mechanisms for SNAIL in cancers, resulting in the acquisition of a new therapeutic strategy for cancer progression by targeting SNAIL
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
