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.