CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16INK4a

Wenqi Du; Zongxiang Liu; Wentao Zhu; Tongtong Li; Zhiman Zhu; Lulu Wei; Jun Song; Dongsheng Pei

doi:10.20892/j.issn.2095-3941.2018.0410

CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16^INK4a

Cancer Biol Med. 2019 Aug;16(3):514-529. doi: 10.20892/j.issn.2095-3941.2018.0410.

Authors

Wenqi Du^{1

2}, Zongxiang Liu³, Wentao Zhu¹, Tongtong Li¹, Zhiman Zhu¹, Lulu Wei¹, Jun Song^{4

5}, Dongsheng Pei¹

Affiliations

¹ Department of Pathology, Xuzhou Medical University, Xuzhou 221004, China.
² Department of Anatomy, Xuzhou Medical University, Xuzhou 221004, China.
³ Department of Periodontal Mucosal Diseases, the Affiliated Xuzhou Stomatological Hospital of Xuzhou Medical University, Xuzhou 221002, China.
⁴ Department of General Surgery, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
⁵ Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou 221002, China.

PMID: 31565481
PMCID: PMC6743625
DOI: 10.20892/j.issn.2095-3941.2018.0410

Abstract

Objective: CSN6 is a vital subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is responsible for development disorders and promotes ubiquitin-26S 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; REGγ; gastric cancer; p16; proliferation.