Abstract
Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. Most endometrial cancer cases are diagnosed at an early stage and have good prognosis. Unfortunately a subset of patients with early stage and low grade disease experience recurrence for reasons that remain unclear. Recurrence is often accompanied by chemoresistance and high mortality.Deubiquitinating enzymes (DUBs) are key components of the ubiquitin-dependent protein degradation pathway and act as master regulators in a number of metabolic processes including cell growth, differentiation, and apoptosis. DUBs have been shown to be upregulated in a number of human cancers and their aberrant activity has been linked to cancer progression, initiation and onset of chemoresistance. Thus, selective inhibition of DUBs has been proposed as a targeted therapy for cancer treatment.This study suggests the DUB USP14 as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence. Further USP14 is expressed along with the marker of proliferation Ki67 in endometrial cancer cells in situ. Lastly, pharmacological targeting of USP14 with the FDA approved small-molecule inhibitor VLX1570, decreases cell viability in chemotherapy resistant endometrial cancer cells with a mechanism consistent with cell cycle arrest and caspase-3 mediated apoptosis.
Highlights
Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States with an estimated 55,000 new cases in 2015 [1]
This study suggests the Deubiquitinating enzymes (DUBs) Ubiquitin-Specific Protease 14 (USP14) as a promising biomarker for stratifying endometrial cancer patients at diagnosis based on their risk of recurrence
We show that higher expression levels of USP14 are independently associated with recurrence in a retrospective cohort of women with stage I endometrial adenocarcinoma
Summary
Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States with an estimated 55,000 new cases in 2015 [1]. Type II endometrial adenocarcinomas include non-endometrioid, high grade, TP53-mutated, hormone-receptor negative cancer and are associated with poor prognosis [7, 8] These risk groups fail to predict recurrence in some women as 15% of women with endometrioid endometrial cancer (Type 1) will experience recurrence and risk stratification based on histology or grade alone may fail to capture this subset of women [3, 9]. We show that pharmacological inhibition of USP14 severely affects the viability of carboplatin resistant endometrial cancer cells with a mechanism consistent with arrest of the cells in the G2/M phase of the cell cycle followed by caspase-3 mediated onset of apoptosis In light of these findings, we suggest that USP14 is a novel potential biomarker of recurrence in endometrial cancer, as well as a molecular target for its treatment
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