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

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journal contribution
posted on 26.04.2022, 13:36 by 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, Axel Behrens
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.

Funding

Crick (Grant ID: 10039, Grant title: Behrens FC001039) Crick (Grant ID: 10011, Grant title: STP Proteomics) Crick (Grant ID: 10012, Grant title: STP Metabolomics) Crick (Grant ID: 10008, Grant title: STP High Throughput Screening) Crick (Grant ID: 10009, Grant title: STP Experimental Histopathology) Crick (Grant ID: 10002, Grant title: STP Bioinformatics & Biostatistics) Engineering and Physical Sciences Research Council (Grant ID: EP/T003103/1, Grant title: EPSRC EP/T003103/1) European Commission (Grant ID: 749108 - BRECASTEM, Grant title: EC 749108 - BRECASTEM) Crick (Grant ID: 10501, Grant title: Ratcliffe FC001501)

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