OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in renal cell carcinoma

Abstract

Background: OTUB1 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding proteins)mediated deubiquitination of FOXM1 (Forkhead box M1) participates in carcinogenesis of various tumors. We aim to investigate the effect and mechanism of OTUB1/FOXM1 on RCC (renal cell carcinoma) progression. Expression levels of OTUB1 in RCC tissues and cell lines were examined by qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. Cell proliferation was measured with CCK8 (Cell Counting Kit-8) and colony formation assays. Wound healing and transwell assays were used to determine cell migration and invasion, respectively. The effect of OTUB1 on FOXM1 ubiquitination was examined by Immunoprecipitation. Western blot was used to uncover the underlying mechanism. In vivo subcutaneous xenotransplanted tumor model combined with immunohistochemistry and western blot were used to examine the tumorigenic function of OTUB1. Results: OTUB1 was up-regulated in RCC tissues and cell lines, and was associated with poor prognosis of RCC patients. Knockdown of OTUB1 inhibited cell viability and proliferation, as well as migration and invasion of RCC cells. Mechanistically, knockdown of OTUB1 down-regulated FOXM1 expression by promoting its ubiquitination. Downregulation of FOXM1 inhibited ECT2 (epithelial cell transforming 2)-mediated Rho signaling. Moreover, the inhibition of RCC progression caused by OTUB1 knockdown was reversed by FOXM1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that knockdown of OTUB1 could suppress in vivo RCC growth via downregulation of FOXM1-mediated ECT2 expression. Conclusions: OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in RCC, providing a new potential therapeutic target for RCC treatment.

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

“…For further explanation, we transfected PC3 and C4-2 cells with OTUB1 siRNA, and the expression level of OTUB1 was decreased distinctly compared with the control group ( Figure 2B ). Recent studies have shown that OTUB1 is highly expressed in invasive tumor cells and plays an important role in its proliferation and invasion (Zhou et al, 2014 , 2019 , 2020 ; Weng et al, 2016 ; Yuan et al, 2017 ; Sun et al, 2020 ). The results showed that the migration and invasion ability of PC3 and C4-2 cells was significantly enhanced in increased OTUB1 group compared with control group ( Figures 2C,E ).…”

“…The next aim of our research focuses on the relationship between OTUB1 and ubiquitin ligases. Not only prostate cancer and the above-mentioned cancers, Kai Zhou et al found that OTUB1 could promote the progression of renal cell carcinoma via mediating the deubiquitination of FOXM1 and up-regulating the expression of ECT-2 (K. Zhou et al, 2020 ). Other researchers have proved that SP1 regulates the progression of non-small-cell lung cancer by recruiting OTUB1 (Xie et al, 2019 ).…”

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

“…Deubiquitination of FOXM1 by UCHL3 was also shown to promote pancreatic cancer progression and gemcitabine resistance ( 146 ). Also, a recent study showed that OTUB1 mediated deubiquitination of FOXM1 promotes renal cell carcinoma via upregulation of ECT 2 ( 149 ).…”

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

“…Recent studies have shown that OTUB1 is highly expressed in invasive tumor cells and plays an important role in their proliferation and invasion (16)(17)(18)(32)(33)(34). The migration experiment results of this project showed that in PC3 and C4-2 cells of prostate cancer, the migration and invasion ability of OTUB1 overexpression cells was signi cantly enhanced compared with control cells (Fig 2C,2E).…”

“…Not only prostate cancer and above mentioned cancers, recently, Kai Zhou et al had found that OTUB1 could promote the progression of renal cell carcinoma via mediating deubiquitination of FOXM1 upregulated the expression of ECT-2(32). Other researchers had proved that SP1 regulated the progression of non-small-cell lung cancer by recruiting OTUB1(53).…”