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.
Highlights
The ubiquitin-proteasome system (UPS) is involved in many biological processes, including cell cycle progression, signal transduction, immune response, stress response, and tumorigenesis (Hershko and Ciechanover, 1998)
To investigate the regulation of histone-modifying enzymes by Ubiquitinspecific protease 7 (USP7), we tested the interaction between several histone-modifying enzymes and USP7 using the immunoprecipitation assay and found that enhancer of zeste homolog 2 (EZH2) interacts with USP7 (Figure S1A and B)
The interaction of USP7 with EZH2 has been previously reported by de Bie et al (2010); they demonstrated the interaction of USP7 with Polycomb group (PcG) proteins, including RING1B, RING1A, SUZ12, EZH2, and BMI1, using the GST pulldown assay
Summary
The ubiquitin-proteasome system (UPS) is involved in many biological processes, including cell cycle progression, signal transduction, immune response, stress response, and tumorigenesis (Hershko and Ciechanover, 1998). The properties of target proteins, such as stability, function, and subcellular localization, are changed by ubiquitination. Deubiquitination, the cleavage of Ub moieties, is mediated by deubiquitinating enzymes (DUBs) (Kim et al, 2003), and this process reverses the functional changes caused by ubiquitination. The DUBs are one of the major regulatory axes of UPS and are important players in many cellular processes, including cancer development (Hanpude et al, 2015; Wei et al, 2015). Dysregulated or mutated histonemodifying enzymes disturb the normal epigenetic pattern of histones and produce a genetic environment that is favorable for tumor development and progression
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