Protein Disulfide Isomerase Family A Member 6 (PDIA6) is an endoplasmic reticulum protein that is capable of catalyzing protein folding and disulfide bond formation. Abnormally elevated expression of PDIA6 has been reported to predict poor outcomes in various cancers. Herein, gain-of- and loss-of-function experiments were performed to investigate how PDIA6 participated in the carcinogenesis of pancreatic cancer (PC). By analyzing the protein expression of PDIA6 in 28 paired PC and para carcinoma specimens, we first found that PDIA6 expression was higher in PC samples. Both the overall survival and disease-free survival rates of PC patients with higher PDIA6 expression were poorer than those with lower PDIA6 ( n = 178). Furthermore, knockdown of PDIA6 impaired the malignancies of PC cells — suppressed cell proliferation, invasion, migration, cisplatin resistance, and xenografted tumor growth. PDIA6-silenced PC cells were more sensitive to cytotoxic natural killer (NK) cells. Overexpression of PDIA6 had opposite effects on PC cells. Interestingly, COP9 signalosome subunit 5 (CSN5), a regulator of E3 ubiquitin ligases known to promote deubiquitination of its downstream targets, was demonstrated to interact with PDIA6, and its expression was increased in PC cells overexpressing PDIA6. Additionally, PDIA6 overexpression promoted deubiquitination of β-catenin and PD-L1 and subsequently upregulated their expression in PC cells. These alterations were partly reversed by CSN5 shRNA. Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5-regulated deubiquitination of β-catenin and PD-L1. Our findings suggest PDIA6 as a potential target for the treatment of PC.
Cao Zhu,Yang Shizhou,Zou Jian,Jin Ye,Zhang Yanan,Chen Tingting,Shen Yuanming
Cervical cancer (CC) remains a significant global health challenge. A deeper understanding of the molecular mechanisms driving CC progression is crucial for developing improved therapeutic strategies. CSN5 is vital in cell functions and cancer, but its role in CC is unclear. This study aims to explore CSN5’s role and its target gene in CC progression, assessing their potential as therapeutic targets. We employed an integrated approach combining bioinformatics analysis, proteomic profiling, and in vitro and in vivo functional assays. Immunohistochemistry was used to analyze CSN5 and ENO3 expression in CC and normal tissues. CSN5 upregulation was associated with advanced clinical stage and poor differentiation. Furthermore, CSN5 overexpression enhanced cellular proliferation and glycolytic metabolism but, paradoxically, suppressed migration, invasion, and the epithelial-mesenchymal transition (EMT). These pro-tumorigenic effects were confirmed in vivo, and the glycolytic inhibitor 2-DG was found to reverse the phenotypes induced by CSN5. Protein sequencing highlighted ENO3’s role in CSN5-mediated tumorigenesis, regulating EMT and glycolysis by stabilizing its ubiquitination degradation through CSN5. Crucially, silencing ENO3 attenuated the oncogenic effects of CSN5 both in vitro and in vivo. Our findings unveil a novel mechanistic paradigm in which CSN5 promotes CC progression by co-opting ENO3 to enhance glycolytic flux while concurrently suppressing cell motility. This study not only deepens the understanding of CC pathogenesis but also identifies the CSN5-ENO3 axis as a promising target for novel therapeutic interventions. Graphical abstract
危险品化学品经营许可证（带存储）