Abstract
BackgroundCSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet.MethodsData from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 and clinical relevance in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR–CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. The biological behaviors were analyzed by CCK8, clone formation assay, 3-D spheroid generation assay and cell cycle assay. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. MLN4924 was given in Siha and Hela with CSN5 overexpression.ResultsWe found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells.ConclusionsOur findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.
Highlights
CSN5, a member of Cop9 signalosome, is essential for protein neddylation
Elevated CSN5 expression predicts poor prognosis in cervical cancer We analyzed the expression of CSN5 in cervical cancer by searching the public database
From the GSE6791, GSE7410 and TCGA datasets, we found that the level of CSN5 expression was significantly up-regulated in cervical cancers compared with normal tissue (Fig. 1A–C)
Summary
CSN5, a member of Cop signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. The role of CSN5 has not been investigated in cervical cancer yet. In China, cervical carcinoma had an estimated incidence of 9.89 and mortality of 3.05 per 100,000 in 2015, ranking the leading cancers. Zhang et al Cancer Cell Int (2021) 21:369 physiological processes by adding ubiquitin-like protein NEDD8 to cullin. MLN4924 (pevonedistat) is a small molecular inhibitor that effectively disrupts neddylation by targeting NEDD8-activating enzyme (NAE) . MLN4924 has been reported to have anticancer effects on various cancers, including cervical cancer [17, 18]. It is applied as a promising anti-cancer drug in clinical I/II trials [19]. Molecules that modulate the pharmacological effects of MLN4924 have not been fully investigated yet
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