USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer

Jessica K. Nelson, May Zaw Thin, Theodore Evan, Steven Howell, Mary Wu, Bruna Almeida, Nathalie Legrave, Duco S. Koenis, Gabriela Koifman, Yoichiro Sugimoto, Miriam Llorian Sopena, James MacRae, Emma Nye, Michael Howell, Ambrosius P. Snijders, Andreas Prachalias, Yoh Zen, Debashis Sarker and Axel Behrens ()
Additional contact information
Jessica K. Nelson: Adult Stem Cell Laboratory, The Francis Crick Institute
May Zaw Thin: Adult Stem Cell Laboratory, The Francis Crick Institute
Theodore Evan: Adult Stem Cell Laboratory, The Francis Crick Institute
Steven Howell: Proteomics, The Francis Crick Institute
Mary Wu: High Throughput Screening, The Francis Crick Institute
Bruna Almeida: Experimental Histopathology, The Francis Crick Institute
Nathalie Legrave: Metabolomics, The Francis Crick Institute
Duco S. Koenis: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square
Gabriela Koifman: Adult Stem Cell Laboratory, The Francis Crick Institute
Yoichiro Sugimoto: Hypoxia Biology Laboratory, The Francis Crick Institute
Miriam Llorian Sopena: Bioinformatics and Biostatistics, The Francis Crick Institute
James MacRae: Metabolomics, The Francis Crick Institute
Emma Nye: Experimental Histopathology, The Francis Crick Institute
Michael Howell: High Throughput Screening, The Francis Crick Institute
Ambrosius P. Snijders: Proteomics, The Francis Crick Institute
Andreas Prachalias: Hepatobiliary and Pancreatic Surgery, King’s College Hospital, Denmark Hill
Yoh Zen: Institute of Liver Studies, King’s College Hospital, Denmark Hill
Debashis Sarker: School of Cancer and Pharmaceutical Sciences, King’s College Hospital, Denmark Hill
Axel Behrens: Adult Stem Cell Laboratory, The Francis Crick Institute

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

Date: 2022
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DOI: 10.1038/s41467-022-29684-9

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