CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16~(INK4a)

【Author】

Wenqi Du;Zongxiang Liu;Wentao Zhu;Tongtong Li;Zhiman Zhu;Lulu Wei;Jun Song;Dongsheng Pei;Department of Pathology, Xuzhou Medical University;Department of Anatomy, Xuzhou Medical University;Department of Periodontal Mucosal Diseases, the Affiliated Xuzhou Stomatological Hospital of Xuzhou Medical University;Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University;Institute of Digestive Diseases, Xuzhou Medical University;

【Institution】

Department of Pathology, Xuzhou Medical University;Department of Anatomy, Xuzhou Medical University;Department of Periodontal Mucosal Diseases, the Affiliated Xuzhou Stomatological Hospital of Xuzhou Medical University;Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University;Institute of Digestive Diseases, Xuzhou Medical University;

【Abstract】

Objective: CSN6 is a vital subunit of the constitutive photomorphogenesis 9(COP9) signalosome(CSN), which is responsible for development disorders and promotes ubiquitin-26 S proteasome-dependent degradation in vitro and vivo.Its role in the tumor development of gastric cancer remains unclear.In this study, we investigated the role of CSN6 in gastric cancer progression.Methods: Human gastric cancer samples were collected and immunohistochemistry was performed to identify the role of CSN6 in gastric cancer.The cell proliferation was measured by CCK-8 and the EdU incorporation method.Immunofluorescence localization and a co-immunoprecipitation study were used to show the interaction between the protein CSN6 and p16.Ubiquitination assay was performed to validate whether ubiquitination is involved in CSN6-mediated p16 degradation.BALB/c nude mice were used to produce a tumor model in order to test the effect of CSN6 on cancer growth in vivo.Results: CSN6 expression was dramatically increased in gastric cancer tissues compared with paired adjacent non-tumor tissues and CSN6 was correlated with worse overall and disease-specific survival.Additionally, we also found that CSN6 downregulated p16 protein expression, thereby promoting gastric cancer cell growth and proliferation.Moreover, CSN6 interacted with p16 and a proteasome activator REGγ(PA28γ), thereby facilitating ubiquitin-independent degradation of p16.Conclusions: CSN6 promoted the loss of p16-mediated tumor progression and played an important role in regulating ubiquitin-independent proteasomal degradation of p16.

【Keywords】

CSN6;;gastric cancer;;proliferation;;p16;;REGγ

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