Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

Suet-Ying Kwan,Samuel C Mok,Karen H Lu,Angela Rynne-Vidal,Tsz-Lun Yeung,Melinda S Yates,Rosemarie E Schmandt,John I Risinger,Hui-Kuan Lin,Kwong-Kwok Wong,Chi-Lam Au-Yeung

doi:10.3390/cancers12010118

Abstract

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.

Highlights

Endometrial cancer is the most common gynecologic malignancy in the United States [1] and is categorized into two broad subtypes based on histopathology [2]
To identify genes contributing to the increased aggressiveness of uterine serous carcinoma (USC), we used the The Cancer Genome Atlas (TCGA) data set to find genes that are upregulated in USC and associated with poorer overall survival
Grade 3 endometrioid carcinomas (EEC) was not included in the EEC group, as we observed an overlap between the RNA expression profiles of grade 3 EEC and USC based on principal component analysis

Summary

Introduction

Endometrial cancer is the most common gynecologic malignancy in the United States [1] and is categorized into two broad subtypes based on histopathology [2]. Type I tumors are grade 1–2 endometrial endometrioid carcinomas (EEC) with a favorable prognosis, while type II malignancies have a poorer prognosis and include grade 3 endometrioid carcinoma, uterine serous carcinoma (USC). While the majority of tumors are EEC, USC is the most common non-endometrioid subtype and the most aggressive, accounting for approximately 10% of all endometrial cancers but 40% of deaths [3]. Presence of extra-uterine disease and suboptimal cytoreduction are risk factors for overall survival [6,7], but both early- and late-stage USC behave aggressively, with a tendency toward lymphovascular invasion, Cancers 2020, 12, 118; doi:10.3390/cancers12010118 www.mdpi.com/journal/cancers

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