Abstract
Globally, epithelial ovarian cancer (EOC) is the most common gynecological malignancy with poor prognosis. The expression and oncogenic roles of ubiquitin specific peptidase 5 (USP5) have been reported in several cancers except EOC. In the current study, USP5 amplification was highly prevalent in patients with EOC and associated with higher mRNA expression of USP5. USP5 amplification and overexpression was positively correlated with poor prognosis of patients of ovarian serous carcinomas. Disruption of USP5 profoundly repressed cell proliferation by inducing cell cycle G0/G1 phase arrest in ovarian cancer cells. Additionally, USP5 knockdown inhibited xenograft growth in nude mice. Knockdown of USP5 decreased histone deacetylase 2 (HDAC2) expression and increased p27 (an important cell cycle inhibitor) expression in vitro and in vivo. The promoting effects of USP5 overexpression on cell proliferation and cell cycle transition, as well as the inhibitory effects of USP5 overexpression on p27 expression were mediated by HDAC2. Moreover, USP5 interacted with HDAC2, and disruption of USP5 enhanced the ubiquitination of HDAC2. HDAC2 protein was positively correlated USP5 protein, and negatively correlated with p27 protein in ovarian serous carcinomas tissues. Collectively, our data suggest the oncogenic function of USP5 and the potential regulatory mechanisms in ovarian carcinogenesis.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy [1]
copy-number variation (CNV) analysis performed on The Cancer Genome Atlas (TCGA) ovarian serous carcinomas dataset revealed that 8 members of ubiquitin specific protease family (USP) displayed copy-number amplification in patients with ovarian serous carcinomas (n=579), and ubiquitin specific peptidase 5 (USP5) had the highest amplification rate (Figure 1A)
CNV on mRNA expression were evaluated by GISTIC analysis, and the results showed that USP5 amplification was associated with higher mRNA expression of USP5 in ovarian serous carcinomas patients (Figure 1C)
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy [1]. Serous ovarian carcinoma accounts for about 60% of EOC and represents the most common type of EOC [2]. The currently established therapy of EOC includes surgery, platinum plus paclitaxel-based chemotherapy and radiation therapy [3]. Because of the lack of specific symptoms and effective diagnosis methods, a majority of patients are diagnosed at an advanced stage (stage III or stage IV). Much development has been made, the prognosis for patients with advanced stage of EOC is still unfavorable. EOC represents the fifth leading cause of malignancy-related death in women worldwide [4]. It is urgently needed to www.aging-us.com gain a better understanding of the molecular events that result in the development of EOC
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