USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment
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Rachel Isaksson Vogel1,*, Tanya Pulver1,*, Wiebke Heilmann1,2,*, Ashley Mooneyham1, Sally Mullany1, Xianda Zhao3, Maryam Shahi4, James Richter4, Molly Klein4, Liqiang Chen5, Rui Ding5, Gottfried Konecny6, Stefan Kommoss2, Boris Winterhoff1, Rahel Ghebre1, Martina Bazzaro1
1Masonic Cancer Center and Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, USA
2Department of Women’s Health, University Hospital Tuebingen University, Tuebingen, Germany
3Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
4Department of Pathology and Laboratory Medicine, University of Minnesota, Minneapolis, MN, USA
5Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN, USA
6Gynecologic Oncology, Hematology & Oncology Department, UCLA Medical Center, Santa Monica, CA, USA
*These authors have contributed equally to this work
Martina Bazzaro, e-mail: [email protected]
Keywords: endometrial cancer, VLX1570, recurrence, biomarker, USP14
Received: December 30, 2015 Accepted: March 31, 2016 Published: April 18, 2016
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.
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