YOD1 serves as a potential prognostic biomarker for pancreatic cancer

Abstract

Background Ubiquitination is a basic post-translational modification of intracellular proteins and can be reversed enzymatically by DUBs (deubiquitinating enzymes). More than 90 DUBs have been identified. Among them, the deubiquitinating enzyme YOD1, a member of the ovarian tumor domain protease (OTUs) subfamily, is involved in the regulation of endoplasmic reticulum (ER)-related degradation pathways. In fact, it is reported that YOD1 is an important proliferation and metastasis-inducing gene, which can stimulate the characteristics of cancer stem cells and maintain circulating tumor cells (CTC). However, the expression level, prognostic effect and biological functional mechanism of YOD1 in pancreatic cancer are still unclear. Results In the GEO and TCGA databases, YOD1 mRNA expression is significantly up regulated in a variety of human pancreatic cancer tissues. Survival analysis showed that the up regulation of YOD1 can predict poor prognosis of pancreatic cancer. Cox analysis showed that high YOD1 expression is an independent prognostic factor of pancreatic cancer. ROC analysis shows that YOD1 has significant diagnostic value. The immunohistochemistry (IHC) results showed that the protein expression level of YOD1 in pancreatic cancer tissue was higher than that in neighboring non-pancreatic cancer tissues (P < 0.001). In addition, we found that YOD1 expression is negatively correlated with the infiltration level of CD8 + T cells, macrophages, neutrophils and dendritic cells (DC) in pancreatic cancer. The expression of YOD1 has a strong correlation with the different immune marker sets in PAAD. Co-expression network and functional enrichment analysis indicate that YOD1 may participate in the development of pancreatic cancer through cell adhesion molecules, p53, Hippo, TGF-β and other pathways. The experimental results of EDU, Transwell, Immunohistochemistry (IHC), Western blot and Flow Cytometry indicate that YOD1 is highly expressed in pancreatic cancer cells and pancreatic cancer tissues, and its overexpression can promote the proliferation and metastasis of pancreatic cancer cells and affect the immune microenvironment. Conclusion Our results indicate that YOD1 may be a useful biomarker for the prognosis of human pancreatic cancer, and it may also be a potential molecular target for the diagnosis and treatment of pancreatic cancer.

Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis

“…Differently, we found that YOD1 showed a strong correlation with poor prognosis in TNBC patients. Previous studies have reported the regulatory role of YOD1 in cancer developments, such as, YOD1 suppresses the malignant development of ovarian cancer via binding to miR-4429 [ 42 ] and YOD1 serves as a potential prognostic biomarker for pancreatic cancer through cell adhesion molecules, p53, Hippo, TGF-β and other pathways [ 43 ]. However, no study has reported the effect and mechanism of YOD1 on the development of TNBC.…”

“…YOD1 is a member of the deubiquitinating enzyme family, whose protein comprises three conserved domains: N-terminal UBX domain, central otubain domain and C-terminal C2H2-type Znf domain [ 24 , 33 ]. Some studies have reported that protein domains, accessories to the catalytic core, are required for YOD1 function [ 19 , 33 , 43 ]. YOD1 is associated with p97 to facilitate protein dislocation, in which the dominant negative effect is dependent on the UBX and Zinc finger domains, appended to the N- and C-terminus of the catalytic otubain core domain, respectively [ 24 ].…”

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

“…Recently, however, extensive research has been performed on YOD1 regulation using different miRNAs. Several studies have reported correlations between YOD1 expression and various cancers including pancreatic and ovarian cancers 258,259 . In addition to YOD1, ATAXIN‐3 represents a major mammalian DUB.…”

“…Ubqln2 À/À mice 288 Ubqln2 À/À rats 289 Adult Ubqln2 deficient mice developed hyperactivity HeLa cells 288,290 NSC34 mouse motor neuron cells 288 HEK293 cells 291 Ubiquilin 3 -Ubqln3 298 cancers including pancreatic and ovarian cancers. 258,259 In addition to YOD1, ATAXIN-3 represents a major mammalian DUB. It has also been shown to interact with p97.…”

Ubiquitin signaling in pancreatic ductal adenocarcinoma

“…In addition, YOD1 deubiquitinase is highly expressed in PDAC and accelerates tumor metastasis, although the underlying mechanism remains unclear ( Zhang et al, 2022 ). It is noticeable that USP9X is reported inactivated in more than 50% of PDAC, and its level is inversely associated with metastatic burden in advanced disease, which may result in anoikis ( Perez-Mancera et al, 2012 ) and inhibition of programmed cell death ( Taddei et al, 2012 ).…”