Functional analysis of deubiquitylating enzymes in tumorigenesis and development

The ubiquitin system regulates diverse biological processes, many involved in cancer pathogenesis, by altering the ubiquitination state of protein substrates. This is accomplished by ubiquitin ligases and deubiquitinases (DUBs), which respectively add or remove ubiquitin from substrates to alter their stability, activity, localization and interactions. While lack of catalytic activity makes therapeutic targeting of ubiquitin ligases difficult, DUB inhibitors represent an active area of research and the identification of cancer-associated DUBs may lead to the development of novel therapeutics. A growing body of literature demonstrates that the DUB Otubain 1 (OTUB1) regulates many cancer-associated signaling pathways including MAPK, ERa, epithelial-mesenchymal transition (EMT), RHOa, mTORC1, FOXM1 and P53 to promote tumor cell survival, proliferation, invasiveness and therapeutic resistance. In addition, clinical studies have associated elevated OTUB1 expression with high grade, invasiveness and metastasis in several tumor types including lung, breast, ovarian, glioma, colon and gastric. Interestingly, in addition to catalytic DUB activity, OTUB1 displays a catalytic-independent, non-canonical activity where it inhibits the transfer of ubiquitin onto protein substrates by sequestration of E2 ubiquitin-conjugating enzymes. The aim of this review is to describe the canonical and non-canonical activities of OTUB1, summarize roles for OTUB1 in cancer-associated pathways and discuss its potential therapeutic targeting.

/pdf/otubain-1-a-non-canonical-deubiquitinase-with-an-emerging-3udr4wunte.pdf

Otubain 1: a non-canonical deubiquitinase with an emerging role in cancer.

Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis

Deubiquitinating enzyme OTUB1 in immunity and cancer: Good player or bad actor?

Background: Prostate cancer (PCa) is currently the most common cancer among males worldwide. It has been reported that OTUB1 plays a critical role in a variety of tumors and is strongly related to tumor proliferation, migration, and clinical prognosis. The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism. Methods: Using the TCGA database, we identified that OTUB1 was up-regulated in PCa, and observed severe functional changes in PC3 and C4-2 cells through overexpression or knock down OTUB1. Heterotopic tumors were implanted subcutaneously in nude mice and IHC staining was performed on tumor tissues. The relationship between OTUB1 and cyclin E1 was identified via Western blotting and immunoprecipitations assays. Results: We found that the expression of OTUB1 in PCa was significantly higher than that in Benign Prostatic Hyperplasia (BPH). Overexpression OTUB1 obviously promoted the proliferation and migration of PC3 and C4-2 cells via mediating the deubiquitinated Cyclin E1, while OTUB1 knockout has the opposite effect. The nude mice experiment further explained the above conclusions. We finally determined that OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabling Cyclin E1. Conclusions: Our findings reveal the critical role of OTUB1 in PCa, and OTUB1 promotes the proliferation and progression of PCa via deubiquitinating and stabilizing Cyclin E1. Blocking OTUB1/Cyclin E1 axis or applying RO-3306 could significantly repress the occurrence and development of PCa. OTUB1/Cyclin E1 axis might provide a new and potential therapeutic target for PCa.

/pdf/otub1-promotes-progression-and-proliferation-of-prostate-2mv2ikuj6z.pdf

OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1

OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily Although it has been demonstrated to play important roles in the development of many kinds of cancer, the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples In addition, the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples In the immunohistochemical study, OTUB1 showed high expression in 60 of the 115 cases (522%) The OTUB1 expression level was significantly correlated with many clinicopathological parameters, including TNM stage (P = 0002), histology stage (P = 0002), and metastasis/recurrence (P = 0016) Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] = 0482; confidence interval [CI]: 0311-0748; P = 0001) Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR = 0214; CI: 0126-0364; P < 0001) for HCC patients The ability of HCC cells to undergo proliferation, migration, and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA) OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients Overexpression of OTUB1 in HCC could be a novel, effective, and supplementary biomarker for HCC because it plays a vital role in the progression of HCC

/pdf/expression-of-otub1-in-hepatocellular-carcinoma-and-its-23lm1op31k.pdf

Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.

Background The short- and long-term prognoses are unclear following laparoscopic major hepatectomy (LMH) for hepatocellular carcinoma (HCC). We performed a meta-analysis to compare the surgical and oncological outcomes of LMH vs. open major hepatectomy (OMH) in patients with HCC. Methods All studies comparing LMH with OMH for HCC published until April 2019 were identified independently by searching PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. We analyzed data for surgical and oncological outcomes, namely, operative time, intraoperative blood loss, blood transfusion rate, postoperative morbidity, major complications, mortality, hospital stay, margin distance, negative margin rate, long-term overall survival, and corresponding disease-free survival (DFS). Results We included 13 studies involving 1,225 patients with HCC (LMH: 534 patients; OMH: 691 patients) in the meta-analysis. Regarding short-term outcomes, the pooled data showed that LMH was associated with longer operative time [weighted mean difference (WMD): 72.14 min; 95% confidence interval (CI): 43.07–101.21; P<0.00001], less blood loss (WMD: −102.32 mL; 95% CI: −150.99 to −53.64; P<0.0001), shorter hospital stay (WMD: −3.77 d; 95% CI: −4.95 to −2.60; P<0.00001), lower morbidity [risk difference (RD): −0.01; 95% CI: −0.16 to −0.06; P<0.00001], and lower major complication rates (RD: −0.08; 95% CI: −0.11 to −0.05; P<0.00001). However, the need for blood transfusion (RD: −0.01; 95% CI: −0.06 to 0.05; P=0.78), mortality (RD: −0.01; 95% CI: −0.02 to 0.01; P=0.57), margin distance (WMD: 0.05 mm; 95% CI: −0.1 to 0.19; P=0.52), and negative margin rate (RD: 0.01; 95% CI: −0.03 to 0.05; P=0.65) were significantly comparable between the two groups. Regarding long-term outcomes, there was no difference in 3-year DFS [hazard ratio (HR): 0.99; 95% CI: 0.72–1.37; P=0.95], 3-year overall survival (HR: 1.25; 95% CI: 0.70–2.21; P=0.45), 5-year DFS (HR: 0.94; 95% CI: 0.64–1.38; P=0.76), and 5-year overall survival (HR: 0.94; 95% CI: 0.45–1.99; P=0.88). Conclusions LMH can be performed as safely as OMH in select patients and provides improved short-term surgical outcomes without affecting long-term survival. However, confirming our results requires more evidence from high-quality and prospective randomized controlled trials.

/pdf/surgical-and-oncological-outcomes-after-laparoscopic-vs-open-3xacugyvjc.pdf

Surgical and oncological outcomes after laparoscopic vs. open major hepatectomy for hepatocellular carcinoma: a systematic review and meta-analysis

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Expression of OTUB1 in hepatocellular carcinoma and its effects on HCC cell migration and invasion.

Surgical and oncological outcomes after laparoscopic vs. open major hepatectomy for hepatocellular carcinoma: a systematic review and meta-analysis