Ma Jia,Zhou Wenyang,Yuan Yifeng,Wang Baosheng,Meng Xiangpeng
Proteasome 26S subunit, non-ATPase 12 (PSMD12) genes have been implicated in several types of malignancies but the role of PSMD12 in pancreatic cancer (PC) remains elusive. Bioinformatics analysis showed that PSMD12 was highly expressed in PC patients and was associated with shorter overall survival. PSMD12 was also shown to be highly expressed in PC tissues and cell lines. Upregulated PSMD12 showed enhanced cell viability, increased colony formation rate and upregulated levels of PCNA and c-Myc, while the inhibition of PSMD12 abated these levels. PSMD12 knockdown promoted cell apoptosis. The results of xenografts in nude mice confirmed that PSMD12 promoted PC tumor growth in vivo. Protein ‒ protein interaction network and functional enrichment analyses implied that PSMD12 may have a connection with cyclin-dependent kinase inhibitor 3 (CDKN3). Co‑immunoprecipitation and western blot results confirmed that PSMD12 could interact with and abate the ubiquitination level of CDKN3, thus stabilizing the CDKN3 protein. Rescue assays showed that PSMD12 overexpression caused cell proliferation and that knockdown-induced cell apoptosis could be reversed by CDKN3 regulation. This work reveals the essential roles of PSMD12 in the proliferation and apoptosis of PC development. PSMD12 may regulate CDKN3 expression by interacting with and abating the ubiquitination level of CDKN3, thereby participating in the malignant behavior of PC.
Dysregulation of deubiquitinase or ubiquitinase-mediated protein expression contributes to various diseases, including cancer. In the present study, we identified GID2 , a subunit of the glucose-induced degradation-deficient (GID) complex that functions as an E3 ubiquitin ligase, as a potential key candidate gene in pancreatic cancer (PC) progression. The functional role and potential mechanism of GID2 in PC progression were investigated. Integrated bioinformatics analysis was performed to identify differentially expressed genes in PC based on the Gene Expression Profiling Interactive Analysis data sets. We found that GID2 was upregulated in PC tissues and that a high level of GID2 expression in clinical PC samples was positively associated with tumor stage and poor survival. Functional assays elucidated that GID2 expression promoted cell growth in vitro and accelerated tumor growth in vivo. GID2 knockdown effectively attenuated the malignant behaviors of PC cells and tumor formation. Furthermore, the protein network that interacted with the GID2 protein was constructed based on the GeneMANIA website. Cyclin-dependent kinase inhibitor 3 (CDKN3), a cell cycle regulator, was identified as a potential target of the GID2 protein. We revealed that GID2 positively regulated CDKN3 expression and inhibited CDKN3 ubiquitination. Furthermore, CDKN3 downregulation reversed the promoting effects of GID2 on PC progression. Therefore, the present study demonstrated that GID2 might regulate PC progression by maintaining the stability of the CDKN3 protein. These findings highlight the potential roles of the GID2/CDKN3 axis as a potential therapeutic target in PC.
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