<p>DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma</p>

Abstract

Background: Here, we probed the action mechanism of ubiquitin-specific processing proteases 17 (DUB3) in the evolution of oral squamous cell carcinoma (OSCC). Methods: The expression of genes were calculated by qRT-PCR, and proteins were assessed by Western blot and immunohistochemistry. The cells viability and proliferation were checked by MTT and EdU assay, respectively. Flow cytometry was implemented to detect the cell cycle and apoptosis. The activity of EZH2 gene promoter was measured by luciferase reporter assay. Co-immunoprecipitation assay was used to ensure the ubiquitination of bromodomain-containing protein 4 (BRD4). The cell apoptosis of tumor tissues was assessed by TUNEL assay. Results: DUB3 was overexpressed in OSCC tissues and cell lines, and negatively correlated with patient's survival time. DUB3 downregulation could effectively curb OSCC cells viability and proliferation, promote cell apoptosis and the expression of cleaved-caspase-3, cleaved PARP and p21, while inhibit cyclin D1. Besides, DUB3 production was positivity correlated with enhancer of zeste homolog-2 (EZH2) and BRD4. BRD4 downregulation could repress DUB3-induced EZH2 production, and MG132 reversed DUB3 decreasingmediated BRD4 downregulation. Downregulation of DUB3 promoted BRD4 ubiquitination. DUB3 promoted OSCC cells proliferation, while suppressing apoptosis via facilitating EZH2 production. At last, in vivo experiment indicated that the downregulation of DUB3 significantly inhibited the growth of xenograft tumor. Conclusion: In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4-mediated upregulation of EZH2. Our study indicated that DUB3 may be an effective anti-cancer target for OSCC therapy.

Ubiquitin–proteasome system-targeted therapy for uveal melanoma: what is the evidence?

“…Therefore, EZH2 is considered a druggable target in metastatic UM. Furthermore, an increasing number of DUBs, including USP21 [135], UPS44 [136], and DUB3 [137], have been shown to deubiquitinate and stabilize EZH2, resulting in malignancy, which suggests that inhibition of various DUBs and subsequent degradation of EZH2 might be promising targeted therapies in UM.…”

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

“…By inhibiting BRD4 degradation, DUB3 enhanced the expression of EZH2 in OSCC, promoted cell growth and inhibited apoptosis. This indicates that decreasing DUB3 could inhibit OSCC cell proliferation and promote cell apoptosis (50,51). Overall, DUB3 stabilizes BRD4 through deubiquitination and promotes cancer progression, suggesting that DUB3 may be an effective anticancer target for cancer therapy.…”

“…A recent study reported that DUB3 binds to and promotes the deubiquitination and stabilization of BRD4 and protects prostate cancer cells from BETis by promoting BRD4 deubiquitination (43) (Figure 2). Other studies have shown that DUB3 is overexpressed in oral squamous cell carcinoma (OSCC) tissues and cell lines and is negatively correlated with patient survival time (50,51). By inhibiting BRD4 degradation, DUB3 enhanced the expression of EZH2 in OSCC, promoted cell growth and inhibited apoptosis.…”

The role of the deubiquitinating enzyme DUB3/USP17 in cancer: a narrative review

“…DUB3 is overexpressed in oral squamous cell carcinoma (OSCC) tissues and cell lines, and it has a negative effect on the survival of patients with OSCC. Mechanistically, DUB3 promotes the proliferation of OSCC cells and inhibits apoptosis by triggering the expression of enhancer of zeste homolog-2 (EZH2) by suppressing ubiquitin-mediated bromodomain-containing protein 4 (BRD4) degradation [ 37 ].…”