BACKGROUND: Ubiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear.
RESULTS: In this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect.
CONCLUSIONS: Taken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.

Proteasome 26S subunit, non-ATPase 7 (PSMD7) is a deubiquitinating enzyme that is involved in the stability of ubiquitinated proteins and participates in the development of multiple types of cancer. The roles of PSMD7 and its potential mechanisms in bladder cancer (BC) remain elusive.
In this study, we identified that PSMD7 was overexpressed in BC tissues based on gene expression omnibus (GEO) database and TNMplot web. To investigate the functional role of PSMD7, two BC cell lines, T24 and 5637, were selected. The cells were transfected with vectors containing short hairpin RNAs against PSMD7 or plasmids containing full-length PSMD7 to knockdown or overexpress PSMD7.
Our results revealed that silencing PSMD7 inhibited cell proliferation, cycle progression, migration, invasion, and promoted cell apoptosis, whereas PSMD7 overexpression led to the opposite effects in the BC cells. Mechanically, PSMD7 influenced the protein expression but not the mRNA expression of the Ras-related protein Rab-1 A (RAB1A). PSMD7 combined with RAB1A and negatively regulated its ubiquitination, indicating that PSMD7 enhanced the stability of RAB1A through post-transcriptional modification. Moreover, the rescue experiment demonstrated that RAB1A was an important downstream effector molecule of PSMD7. Besides, the negative regulation of silencing PSMD7 on tumor growth was confirmed in mice.
Our study substantiated a novel mechanism by which PSMD7 stabilized RAB1A to accelerate the progression of BC.

Testis-specific transcript 10 (Tex10) is a critical factor for pluripotent stem cell maintenance and preimplantation development. Here, we dissect its late developmental roles in primordial germ cell (PGC) specification and spermatogenesis using cellular and animal models. We discover that Tex10 binds the Wnt negative regulator genes, marked by H3K4me3, at the PGC-like cell (PGCLC) stage in restraining Wnt signaling. Depletion and overexpression of Tex10 hyperactivate and attenuate the Wnt signaling, resulting in compromised and enhanced PGCLC specification efficiency, respectively. Using the Tex10 conditional knockout mouse models combined with single-cell RNA sequencing, we further uncover critical roles of Tex10 in spermatogenesis with Tex10 loss causing reduced sperm number and motility associated with compromised round spermatid formation. Notably, defective spermatogenesis in Tex10 knockout mice correlates with aberrant Wnt signaling upregulation. Therefore, our study establishes Tex10 as a previously unappreciated player in PGC specification and male germline development by fine-tuning Wnt signaling.

Proteasome 26S non-ATPase subunit 7 (PSMD7) and forkhead box P3 (FOXP3) have been found to be both upregulated in gastric cancer tissues. FOXP3 was also predicted to have binding sites on PSMD7 promoter. Thus, this study investigated the relationship between PSMD7 and FOXP3 and their roles in gastric cancer. Bioinformatic databases predicted PSMD7 expression in non-cancerous gastric tissue and gastric cancer tissue, as well as the correlation between PSMD7 and the overall/disease free survival. PSMD7 expression in non-cancerous gastric tissue or cells and gastric cancer tissue or cells was detected by qPCR and Western blot. After PSMD7 downregulation by siRNA interference, cell viability, colony-forming capacity and cell apoptosis were analyzed with cell counting kit-8 assay, colony formation assay and terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling. Proliferation and apoptosis markers were assayed by qPCR and Western blot. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed to look at the binding relationship between FOXP3 and PSMD7 promoter. Cell proliferation and apoptosis were examined again after co-transfection of PSMD7 siRNA plasmid and FOXP3 overexpression plasmid. PSMD7 expression was much higher in gastric cancer tissue and cell lines. Interference with PSMD7 decreased gastric cancer cell viability, inhibited their proliferation and colony formation and promoted cell apoptosis. FOXP3 was found to bind to PSMD7 promoter and activate PSMD7 expression. Overexpression of FOXP3 could rescue the effects of PSMD7 knockdown on gastric cancer cells. PSMD7 is involved in the proliferation and apoptosis of gastric cancer cells and can be transcriptionally regulated by FOXP3.

Ubiquitination, a crucial post-translational modification, controls substrate degradation and can be reversed by deubiquitinases (DUBs). An increasing number of studies are showing that DUBs regulate the malignant behavior and chemotherapy resistance of gastric cancer (GC) by stabilizing various proteins. However, the expression level and biological function of the DUB, proteasome 26S subunit, non-ATPase 7 (PSMD7), in GC remains unknown. Herein, we report for the first time that PSMD7 is frequently overexpressed in GC tissues. Elevated levels of PSMD7 were also detected in GC cell lines. Notably, the upregulation of PSMD7 closely correlated with malignant clinical parameters and reduced the survival of GC patients. Functionally, we found that PSMD7 knockdown consistently suppressed the proliferation, migration, and invasion of AGS and SGC-7901 cells. Ectopic expression of PSMD7 facilitated GC cell proliferation and mobility. Based on protein-protein interaction prediction, RAD23 homolog B (RAD23B) protein was identified as a candidate substrate of PSMD7. PSMD7 positively regulated the abundance of RAD23B and xeroderma pigmentosum, complementation group C (XPC) protein in GC cells. The interaction between PSMD7 and RAD23B was confirmed using protein immunoprecipitation. PSMD7 knockdown enhanced the ubiquitination and degradation of RAD23B protein in GC cells. PSMD7 promoted cell viability, apoptosis resistance, and DNA damage repair in GC cells upon cisplatin (DDP) treatment. Moreover, PSMD7 silencing inhibited tumor growth and enhanced the sensitivity of GC cells to DDP treatment in mice. In summary, PSMD7 was highly expressed in GC and contributed to the malignant behavior and DDP resistance of tumor cells by stabilizing RAD23B.

Lung cancer is the second most common cancer in both men and women. The deubiquitinase PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of lung cancer remain largely unknown. In this study, we assessed PSMD7 expression and investigated the underlying molecular events by which PSMD7 regulates tumor progression in non-small cell lung cancer (NSCLC). The results showed that PSMD7 is more highly expressed in NSCLC tissues than in adjacent noncancerous tissues. PSMD7 expression was also closely associated with lymph node invasion and the laterality of the tumor in lung adenocarcinoma (LUAD). A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in LUAD patients, and PSMD7 knockdown significantly reduced cell proliferation and induced G0/G1-phase cell cycle arrest, cell senescence and apoptosis. PSMD7 knockdown inhibited expression of a set of proteins regulating cell cycle progression. Depletion of PSMD7 increased p53 levels and induced p21 and puma expression in a p53-dependent manner. Importantly, knockdown of PSMD7 markedly inhibited LUAD tumor growth in a xenograft mouse model. Taken together, these findings indicate that PSMD7 may serve as a valuable prognostic indicator and potential therapeutic target in LUAD.

Recurrent locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis because of its highly invasive behavior and resistance to conventional intensive chemotherapy. The identification of effective markers for early diagnosis and prognosis is important for reducing mortality and ensuring that therapy for HNSCC is effective. Proteasome 26S subunit, non-ATPase 7 (PSMD7) is an ATP-independent component of the 19S regulatory subunit. The prognostic value of PSMD7 and the association with immune infiltration in HNSCC remains unclear.
The Sangerbox, Oncomine, UALCAN and Human Protein Atlas (HPA) databases were used to examine PSMD7 expression profiles in HNSCC. The CVCDAP was used to analysis the association of PSMD7 with the prognosis of patients with HNSCC. The mechanism was investigated with gene set enrichment analysis (GSEA). The association between expression of PSMD7 and immune infiltration in HNSCC was investigated using the Tumor Immune Estimation Resource (TIMER), TISIDB database and CIBERSORT algorithm.
PSMD7 expression was significantly up-regulated in HNSCC compared with relative normal tissues. In addition, up-regulated PSMD7 expression was associated with various clinicopathological parameters. High expression of PSMD7 suggested inferior survival of HNSCC patients. GSEA and CERES score indicated that PSMD7 was closely correlated with tumor-related signaling pathways and cell survival. Functional analyses revealed that PSMD7 was positively correlated with various infiltration levels. Moreover, PSMD7 influenced the prognosis of HNSCC patients partially via immune infiltration.
Our findings suggest that PSMD7 is associated poor prognosis in patients with HNSCC and plays an important role in tumor-related immune infiltration.

Breast cancer is the most common malignant tumor and the leading cause of cancer-related death in women. The ubiquitin-proteasome system regulates the stability of most proteins controlling various biological processes in human cells. PSMD7, as a core component of the 26S proteasome, is critical for the degradation of ubiquitinated proteins in the proteasome. Currently, PSMD7 expression and its roles in the progression of breast cancer remain largely unknown. In this study, we assessed the level of PSMD7 in breast cancer tissues and investigated the underlying molecular events by which PSMD7 could play a role in tumor progression. The results showed that the PSMD7 level was significantly upregulated in breast cancer tissues. PSMD7 expression was closely associated with tumor subtype, tumor size, lymph node invasion, and TNM stage. A high PSMD7 level predicted poor overall survival (OS) and disease-free survival (DFS) in breast cancer patients. Furthermore, univariate Cox regression analysis indicated that lymph node invasion, distant metastasis, and PSMD7 expression were associated with OS and DFS. Multivariate regression analysis indicated that PSMD7 was an independent predictor of OS (HR=1.310, 95% CI=1.038-1.652). Importantly, PSMD7 knockdown induced cell cycle arrest in the G0/G1 phase, leading to cell senescence and apoptosis. PSMD7 knockdown inhibited the expression of key cell cycle-related proteins and promoted the stability of p21 and p27 in breast cancer cells. PSMD7 may be a valuable prognostic indicator and potential therapeutic target for breast cancer.

PSMD7, a 19S proteasome subunit, is overexpressed in most carcinoma cells. It forms a dimer with PSMD14 that functions in the removal of attached ubiquitin chain. However, there is little knowledge about the cellular mechanism of PSMD7 and its exact biological function, especially in cancer cells. In this study, we explored the role of PSMD7 in proliferation, cell cycle, apoptosis, and proteasomal proteolysis in the esophageal squamous cell carcinoma (ESCC) cell line EC9706. Our results showed that PSMD7 was highly expressed in ESCC cells. Downregulation of PSMD7 by lentivirus-mediated shRNA led to decreased proliferation, increased cell apoptosis, and reduced proteasomal function. Notably, lower expression level of mTOR and p70S6K and suppressed activity of mTOR/p70S6K pathway were detected after PSMD7 downregulation. By contrast, increased expression of p-mTORSer2448 and p-p70S6KThr421/Ser424 was discovered upon PSMD7 overexpression in Het-1A cells. Furthermore, PSMD7 downregulation contributed to decelerated tumor growth, inhibition of proteasomal function, induced cell apoptosis and attenuated activity of mTOR/p70S6K pathway in vivo. These findings suggest that PSMD7 and the mTOR/p70S6K pathway may be a promising candidate for developing therapies for ESCC.

The ATP-dependent degradation of polyubiquitylated proteins by the 26S proteasome is essential for the maintenance of proteome stability and the regulation of a plethora of cellular processes. Degradation of substrates is preceded by the removal of polyubiquitin moieties through the isopeptidase activity of the subunit Rpn11. Here we describe three crystal structures of the heterodimer of the Mpr1-Pad1-N-terminal domains of Rpn8 and Rpn11, crystallized as a fusion protein in complex with a nanobody. This fusion protein exhibits modest deubiquitylation activity toward a model substrate. Full activation requires incorporation of Rpn11 into the 26S proteasome and is dependent on ATP hydrolysis, suggesting that substrate processing and polyubiquitin removal are coupled. Based on our structures, we propose that premature activation is prevented by the combined effects of low intrinsic ubiquitin affinity, an insertion segment acting as a physical barrier across the substrate access channel, and a conformationally unstable catalytic loop in Rpn11. The docking of the structure into the proteasome EM density revealed contacts of Rpn11 with ATPase subunits, which likely stabilize the active conformation and boost the affinity for the proximal ubiquitin moiety. The narrow space around the Rpn11 active site at the entrance to the ATPase ring pore is likely to prevent erroneous deubiquitylation of folded proteins.