Oncotarget

Research Papers:

The deubiquitinating enzyme USP5 promotes pancreatic cancer via modulating cell cycle regulators

Brajesh P. Kaistha, Anja Krattenmacher, Johannes Fredebohm, Harald Schmidt, Diana Behrens, Miriam Widder, Thilo Hackert, Oliver Strobel, Jörg D. Hoheisel, Thomas M. Gress and Malte Buchholz _

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Oncotarget. 2017; 8:66215-66225. https://doi.org/10.18632/oncotarget.19882

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Abstract

Brajesh P. Kaistha1,*, Anja Krattenmacher1,*, Johannes Fredebohm2,*, Harald Schmidt1, Diana Behrens3, Miriam Widder4, Thilo Hackert5, Oliver Strobel5, Jörg D. Hoheisel2, Thomas M. Gress1 and Malte Buchholz1

1Department of Medicine, Division of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, Marburg, Germany

2Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany

3Experimantal Pharmacology and Oncology (EPO Berlin-Buch), Berlin, Germany

4Institute for Bioprocessing and Analytical Measurement Techniques (IBA-Heiligenstadt), Heilbad Heiligenstadt, Germany

5Department of Surgery, University Clinic Heidelberg, Heidelberg, Germany

*These authors have contributed equally to this work

Correspondence to:

Malte Buchholz, email: [email protected]

Keywords: pancreatic cancer, shRNA barcode library screen, ubiquitin specific peptidase, deubiquitinases, molecular pathogenesis

Received: March 31, 2017    Accepted: July 11, 2017    Published: August 03, 2017

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. With an overall five-year survival rate remaining below 6%, there is an explicit need to search for new molecular targets for therapeutic interventions. We undertook a barcode labelled short-hairpin (shRNA) library screen in pancreatic cancer cells in order to identify novel genes promoting cancer survival and progression. Among the candidate genes identified in this screen was the deubiquitinase USP5, which subsequent gene expression analyses demonstrated to be significantly upregulated in primary human pancreatic cancer tissues. Using different knockdown approaches, we show that expression of USP5 is essential for the proliferation and survival of pancreatic cancer cells, tested under different 2D and 3D cell culture conditions as well as in in vivo experiments. These growth inhibition effects upon knockdown of USP5 are mediated primarily by the attenuation of G1/S phase transition in the cells, which is accompanied by accumulation of DNA damage, upregulation of p27, and increased apoptosis rates. Since USP5 is overexpressed in cancer tissues, it can thus potentially serve as a new target for therapeutic interventions, especially given the fact that deubiquitinases are currently emerging as new class of attractive drug targets in cancer.


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