Abstract BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that has long been considered to be a tumor suppressor in various tumors, including renal cell carcinoma, uveal melanoma, mesothelioma, and cutaneous melanoma. However, the involvement of BAP1 in the progression of prostate cancer has not been studied until recently. Herein, we investigated the tumor promoting function of BAP1 in the context of prostate cancer. Analysis of The Cancer Genome Atlas (TCGA) data set showed that prostate cancer patients express high levels of BAP1 mRNA. High BAP1 expression is inversely correlated with disease-free survival in patients with prostate cancer. Among the prostate cell lines tested, BAP1 expression was high in tumorigenic and metastatic cell lines, but was low in normal prostate cell line. Knockdown of BAP1 in PC3 or DU145 cells induced mesenchymal-to-epithelial transition (MET). Further, BAP1-knockdown resulted in decreased migration and invasion of PC3 and DU145 cells. Conversely, overexpression of BAP1 in RWPE1, a normal prostate cell line, induced the migratory and invasive properties. Collectively, our findings identified that BAP1 has a tumor promoting function in prostate cancer cells, and suggest that BAP1 can serve as a potential therapeutic target for prostate cancer.

Abstract Regulation of target proteins by the ubiquitin-proteasome system (UPS) is common in a wide range of cellular events, including transcriptional regulation, cell cycle progression, differentiation, and tumorigenesis. Ubiquitin-specific protease 7 (USP7) has been implicated in tumor development and metastasis in various malignancies through the regulation of target protein stability. In this study, we found that the enhancer of zeste homolog 2 (EZH2), which catalyzes the methylation at lysine 27 of histone H3, is a target of USP7 and is stabilized by USP7-mediated deubiquitination. In prostate cancer cells, the transcriptional repression function of EZH2 was inhibited by USP7-knockdown. Furthermore, ectopic introduction of EZH2 restored the cell migration, invasion, and sphere-forming potential of prostate cancer cells, which had been decreased by USP7-knockdown. Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

Abstract Valproic acid (VPA) is a clinically available histone deacetylase inhibitor with promising anticancer attributes. Recent studies have demonstrated the anticancer effects of VPA on prostate cancer cells. However, little is known about the differential effects of VPA between metastatic and non-metastatic prostate cancer cells and the relationship between the expression of metastasis suppressor proteins and VPA. In the present study, we demonstrate that inhibition of cell viability and invasion by VPA was more effective in the metastatic prostate cancer cell line PC3 than in the tumorigenic but non-metastatic prostate cell line, RWPE2. Further, we identified that the metastasis suppressor NDRG1 is upregulated in PC3 by VPA treatment. In contrast, NDRG1 was not increased in RWPE2 cells. Also, the suppressed invasion of PC3 cells by VPA treatment was relieved by NDRG1 knockdown. Taken together, we suggest that the anticancer effect of VPA on prostate cancer cells is, in part, mediated through upregulation of NDRG1. We also conclude that VPA has differential effects on the metastasis suppressor gene and invasion ability between non-metastatic and metastatic prostate cancer cells.