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

Nat Commun. 2022 Apr 19;13(1):2070. doi: 10.1038/s41467-022-29684-9.

Jessica K Nelson ¹ ², May Zaw Thin ^# ¹ ², Theodore Evan ^# ¹, Steven Howell ³, Mary Wu ⁴, Bruna Almeida ⁵, Nathalie Legrave ⁶, Duco S Koenis ⁷, Gabriela Koifman ¹ ², Yoichiro Sugimoto ⁸, Miriam Llorian Sopena ⁹, James MacRae ⁶, Emma Nye ⁵, Michael Howell ⁴, Ambrosius P Snijders ³, Andreas Prachalias ¹⁰, Yoh Zen ¹¹, Debashis Sarker ¹², Axel Behrens ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1 Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
2 Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
3 Proteomics, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
4 High Throughput Screening, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
5 Experimental Histopathology, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
6 Metabolomics, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
7 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
8 Hypoxia Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
9 Bioinformatics and Biostatistics, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
10 Hepatobiliary and Pancreatic Surgery, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
11 Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
12 School of Cancer and Pharmaceutical Sciences, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
13 Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. [email protected].
14 Cancer Stem Cell Laboratory, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK. [email protected].
15 Imperial College, Division of Cancer, Department of Surgery and Cancer, Imperial College, Exhibition Road, London, SW7 2AZ, UK. [email protected].
16 Convergence Science Centre, Imperial College, Exhibition Road, London, SW7 2BU, UK. [email protected].
# Contributed equally.

PMID: 35440539 DOI: 10.1038/s41467-022-29684-9

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.

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