USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer
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Jessica Nelson May Zaw Thin Theo Evan Steven Howell Mary Wu Bruna Coelho Almeida Nathalie Legrave Duco S Koenis Gabriela Koifman Yoichiro Sugimoto Miriam Llorian Sopena James Macrae Emma Nye Michael Howell Bram Snijders Andreas Prachalias Yoh Zen Debashis Sarker Axel BehrensAbstract
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.
Journal details
Journal Nature Communications
Volume 13
Issue number 1
Pages 2070
Available online
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Publisher website (DOI) 10.1038/s41467-022-29684-9
Europe PubMed Central 35440539
Pubmed 35440539
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- Tumour Biology
- Stem Cells
- Signalling & Oncogenes
- Model Organisms
- Metabolism
- Infectious Disease
- Immunology
- Human Biology & Physiology
- Genome Integrity & Repair
- Genetics & Genomics
- Gene Expression
- Developmental Biology
- Computational & Systems Biology
- Chemical Biology & High Throughput
- Cell Biology
- Biochemistry & Proteomics
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