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

Yihao Liao,Youzhi Wang,Fuling Ma,Keke Wang,Yudong Wu,Ning Jiang,Jie Gao,Miaomiao Wang,Ning Wu,Boqiang Zhong

doi:10.3389/fcell.2020.617758

Abstract

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.

Highlights

Prostate cancer (PCa) is the most common malignant tumor in the United States
Of the up-regulated genes, we observed that the expression of ovarian tumor domain deubiquitination 1 (OTUB1) in PCa was higher than para-carcinoma tissue (Figure 1B)
A Chi-square test was performed, and the results demonstrated that the expression of OTUB1 in PCa groups was higher than that in Benign prostate hyperplasia (BPH) group (X2 = 16.56; P = 0.0024), and the results of ki-67 were consistent with OTUB1 (X2 = 20.2; P = 0.0005)

Summary

Introduction

Prostate cancer (PCa) is the most common malignant tumor in the United States. The prevalence of PCa approximately accounts for 20% of all types of cancers. If detected early and treated aggressively, the 5-year survival rate of PCa will almost reach 100%. Due to the irreplaceable role of androgen receptor (AR) in the development of PCa, the most important and standard treatment is androgen deprivation therapy (ADT) (Murillo-Garzón and Kypta, 2017; Bastos and Antonarakis, 2018). ADT mainly includes drug castration and surgical castration, but most patients eventually develop to castration-resistant prostate cancer (CRPC), even metastasis castration resistant prostate cancer (mCRPC), without effective treatment (Gasnier and Parvizi, 2017; Hossain et al, 2018). There is still a lack of effective and sensitive drugs for prostate cancer, especially the urgent demand for new drugs to treat CRPC (Smolle et al, 2017). The aim of this research is to investigate the regulatory effect of OTUB1 on PCa proliferation and the underlying mechanism

Objectives

Methods

Results

Discussion

Conclusion