Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

Genome-Wide CRISPR/Cas9-Based Screening for Deubiquitinase Subfamily Identifies Ubiquitin-Specific Protease 11 as a Novel Regulator of Osteogenic Differentiation

The osteoblast differentiation capacity of mesenchymal stem cells must be tightly regulated, as inadequate bone mineralization can lead to osteoporosis, and excess bone formation can cause the heterotopic ossification of soft tissues. The balanced protein level of Msh homeobox 1 (MSX1) is critical during normal osteogenesis. To understand the factors that prevent MSX1 protein degradation, the identification of deubiquitinating enzymes (DUBs) for MSX1 is essential. In this study, we performed loss-of-function-based screening for DUBs regulating MSX1 protein levels using the CRISPR/Cas9 system. We identified ubiquitin-specific protease 11 (USP11) as a protein regulator of MSX1 and further demonstrated that USP11 interacts and prevents MSX1 protein degradation by its deubiquitinating activity. Overexpression of USP11 enhanced the expression of several osteogenic transcriptional factors in human mesenchymal stem cells (hMSCs). Additionally, differentiation studies revealed reduced calcification and alkaline phosphatase activity in USP11-depleted cells, while overexpression of USP11 enhanced the differentiation potential of hMSCs. These results indicate the novel role of USP11 during osteogenic differentiation and suggest USP11 as a potential target for bone regeneration.

High Expression of Ubiquitin-Specific Protease 39 and Its Roles in Prognosis in Patients with Hepatocellular Carcinoma

Background. Ubiquitin-specific protease 39 is mainly involved in mRNA splicing and multiple kinds of tumors. Accumulating evidence has shown that USP39 participated in the proliferation and metastasis of hepatocellular carcinoma (HCC). The present study aimed to demonstrate the association between USP39 expression and clinical features and the diagnostic value in HCC based on the Cancer Genome Atlas (TCGA). Methods. A comprehensive analysis for expression of USP39 in HCC was conducted by using multiple databases. The mRNA level of USP39, clinical features, survival rate, and diagnostic value in HCC were analyzed using data from TCGA. The Gene Set Enrichment Analysis (GSEA) was conducted to analyze signaling pathways correlated with USP39 expression in HCC. Results. The mRNA level of USP39 was significantly elevated in HCC. The expression of USP39 showed significant correlation with T stage, pathologic stage, tumor status, age, and histologic grade. Logistic analysis demonstrated that high expression of USP39 was significantly associated with older age, tumor status, advanced pathologic stage, T stage, and higher histologic grade. Univariate Cox regression analysis showed that high expression of USP39 was significantly associated with advanced T stage, pathological stage, and tumor status. Multivariate Cox analysis confirmed the result that USP39 expression was an independent prognostic factor for overall survival (OS) in HCC. Results of Kaplan–Meier curves showed that high expression of USP39 had a significant association with poor OS, disease-free survival (DSS), and progress-free interval (PFI) in HCC. ROC analysis indicated that USP39 could be regarded as a promising marker for distinguishing HCC from nontumor. Conclusion. The increased USP39 might play roles in the progression, diagnosis, and prognosis of HCC.

HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins

HAUSP (herpes virus-associated ubiquitin-specific protease), also known as Ubiquitin Specific Protease 7, plays critical roles in cellular processes, such as chromatin biology and epigenetics, through the regulation of different signaling pathways. HAUSP is a main partner of the “Epigenetic Code Replication Machinery,” ECREM, a large protein complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING), finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60. Due to its deubiquitinase activity and its ability to team up through direct interactions with several epigenetic regulators, mainly UHRF1, DNMT1, TIP60, the histone lysine methyltransferase EZH2, and the lysine-specific histone demethylase LSD1, HAUSP positions itself at the top of the regulatory hierarchies involved in epigenetic silencing of tumor suppressor genes in cancer. This review highlights the increasing role of HAUSP as an epigenetic master regulator that governs a set of epigenetic players involved in both the maintenance of DNA methylation and histone post-translational modifications.