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.
Highlights
Pancreatic cancer remains a major challenge to the biomedical community
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
Since USP5 is overexpressed in cancer tissues, it can 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
Summary
Pancreatic ductal adenocarcinoma (PDAC), the most frequent type of pancreatic cancer, is one of the most lethal malignancies. It is typically characterized by late detection when it usually has metastasized, rendering a majority of patients unfit for surgical resection [1, 2]. Using a variety of different screening strategies, several research groups, including ours, have previously uncovered candidate genes with novel tumorpromoting functions in PDAC, some of which have the potential to be exploited as novel diagnostic and/or therapeutic targets [6,7,8,9,10]. We have employed an unbiased cell-based screening approach to identify additional, hitherto unknown candidate genes in PDAC
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