USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells

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. Ubiquitinspecific 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 USP7knockdown. 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.

Pharmacological Inhibition of USP7 Supresses Growth and Metastasis of Melanoma Cells in Vitro and in Vivo

“…On the other hand, we also found that P22077 lead inhibition of invasion and migration in vitro and in vivo in melanoma. Several substrates contribute to invasion and migration regulated by USP7, such as EZH2 in prostate cancer, LSD1 in glioblastoma [38,39]. Contrary, the role of ROS in triggering signaling pathways, such as activation of MAPK, ERK, JNK, and p-38 MAPK via growth factor-mediated stimulation of receptor tyrosine kinases (RTKs) for cell migration and invasion has been well-established [40].…”

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

“…As one of the most extensively studied inhibitors, USP7 inhibitors have played an effective and highly specific role in many studies. They have a significant inhibitory effect on tumors ( Lee et al, 2020 ; Leger et al, 2020 ; Ohol et al, 2020 ; Schauer et al, 2020a ). P22077/50429 exerted anti-oncogene function in a variety of malignant tumors ( Fan et al, 2013 ; Zhang W. et al, 2020 ) and improved chemoresistance in pancreatic cancer ( Chen H. et al, 2020 ).…”

“…FT827/671 inhibited tumors by degrading the oncogenic E3 ligase MDM2 ( Turnbull et al, 2017 ). In the latest study, P5091 inhibitors showed robust tumor suppression effects in preclinical models of various tumors ( An et al, 2017 ; Wang et al, 2017 ; Hayal et al, 2020 ; He et al, 2020 ; Lee et al, 2020 ). Among these cancers, in colorectal cancer, P5091 improves the antitumor immune response and reduces the proportion of Tregs in tumor xenografts in mice ( Fu et al, 2019 ).…”

Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer

“…We next set out to determine how nuclear p85β stabilizes EZH1 and EZH2 proteins. It has been reported that USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells 32,33 . We thus postulated that nuclear p85β brings USP7 to EZH1 and EZH2, thereby protecting them from ubiquitin-mediated protein degradation.…”