UBE2B promotes ovarian cancer growth via promoting RAD18 mediated ZMYM2 monoubiquitination and stabilization

Abstract

Ubiquitin-conjugating enzyme E2 B (UBE2B) can form a heterodimer with ubiquitin E3 ligase RAD18. In this study, we aimed to explore new substrates of the UBE2B/RAD18 complex and their regulatory effects in ovarian cancer. Protein physical interactions were predicted using GeneMANIA. Serial sections of commercial ovarian cancer tissue arrays were used to check the protein expression of UBE2B, RAD18, and ZMYM2. Immunofluorescence staining and co-immunoprecipitation assays were performed to check their location and interactions. Cycloheximide chase assay was applied to explore the influence of UBE2B and RAD18 on ZMYM2 degradation. Xenograft tumor models were constructed to assess the influence of the UBE2B-ZMYM2 axis on in vivo tumor growth. A strong positive correlation between UBE2B and ZMYM2 and a moderate positive correlation between RAD18 and ZMYM2 were observed in 23 ovarian cancer cases. In CAOV4 and OVCAR3 cells, myc-ZMYM2 interacted with UBE2B and RAD18. UBE2B and ZMYM2 could be detected in the samples immunoprecipitated by anti-RAD18. UBE2B overexpression or knockdown did not alter ZMYM2 mRNA expression. UBE2B overexpression increased ZMYM2 monoubiquitination but reduced its polyubiquitination. RAD18 knockdown impaired UBE2B- induced ZMYM2 monoubiquitination. UBE2B overexpression significantly enhanced the stability of ZMYM2 protein, the effect of which was weakened by RAD18 knockdown. UBE2B overexpression significantly enhanced the growth of xenograft tumors derived from CAOV4 cells. ZMYM2 knockdown remarkedly suppressed tumor growth and impaired the growth-promoting effect of UBE2B overexpression. In conclusion, this study revealed a novel regulatory effect of the UBE2B/RAD18 complex on ZMYM2 monoubiquitination and stability in ovarian cancer.

Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma

“…Emerging functions of ubiquitination modification in CSCs, cellular senescence, and immune infiltration have been affirmed, including roles in tumor metabolism regulation, tumor immune microenvironment modulation, cancer stem cell stemness maintenance, and cellular senescence induction [ 19 ]. Schimmer et al proved that inhibiting the E1-activating enzyme UBA1 reduced leukemia burden and specifically targeted leukemia stem cells [ 20 ]; Ma et al demonstrated that the E2-conjugating enzyme UBE2B promoted ovarian cancer growth [ 21 ]; Wang et al discovered that deleting the E3 ligases TRIM29 inhibited PDAC’s cancer stem cell-like properties by accelerating ISG15 degradation [ 22 ]; Lee et al revealed that USP1-mediated protein stabilisation promoted GSC maintenance and treatment resistance [ 23 ]. Besides, targeting E3 ligase Skp2 attenuates aerobic glycolysis and induces cellular senescence in cancer cells, thereby reducing CSC populations and their function [ 24 ].…”

Diverse roles of UBE2T in cancer (Review)

“…Increasing evidence has verified that E2s show dysregulation in various cancer types, as they are linked to tumor-promoting processes and self-renewal abilities such as dysregulation in DNA repair, cell cycle, apoptosis and oncogenic signalling (10,(17)(18)(19)(20)(21)(22). The dysfunctional status of E2 members is considered a potential biomarker for diagnosis, prognosis and therapy in patients with various cancer types (22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Silver Nanoparticles Induced Changes in DNA Methylation and Histone H3 Methylation in a Mouse Model of Breast Cancer

“…Six of them encode methyltransferases (Setd4, Setdb1, Smyd3, Suv39h1, Suv420h1, and Whsc1), two encode demethylases (Kdm1a and Kdm5b), three encode acetyltransferases (Esco2, Hat1, and Myst3), one encodes histone deacetylase (Hdac5) [25,26], and one encodes DNA methylase (Dnmt1) [27]. Two genes encoding proteins involved in the ubiquitination process were also affected (Ube2b and Usp22) [28,29].…”