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Oncotarget. 2016 May 24;7(21):30962-76. doi: 10.18632/oncotarget.8821.

USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment.

Author information

1
Masonic Cancer Center and Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, USA.
2
Department of Women's Health, University Hospital Tuebingen University, Tuebingen, Germany.
3
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
4
Department of Pathology and Laboratory Medicine, University of Minnesota, Minneapolis, MN, USA.
5
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, USA.
6
Gynecologic Oncology, Hematology & Oncology Department, UCLA Medical Center, Santa Monica, CA, USA.

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.

KEYWORDS:

USP14; VLX1570; biomarker; endometrial cancer; recurrence

PMID:
27121063
PMCID:
PMC5058731
DOI:
10.18632/oncotarget.8821
[Indexed for MEDLINE]
Free PMC Article

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