USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer.
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Embargo End Date
ICR Authors
Authors
Nelson, JK
Thin, MZ
Evan, T
Howell, S
Wu, M
Almeida, B
Legrave, N
Koenis, DS
Koifman, G
Sugimoto, Y
Llorian Sopena, M
MacRae, J
Nye, E
Howell, M
Snijders, AP
Prachalias, A
Zen, Y
Sarker, D
Behrens, A
Thin, MZ
Evan, T
Howell, S
Wu, M
Almeida, B
Legrave, N
Koenis, DS
Koifman, G
Sugimoto, Y
Llorian Sopena, M
MacRae, J
Nye, E
Howell, M
Snijders, AP
Prachalias, A
Zen, Y
Sarker, D
Behrens, A
Document Type
Journal Article
Date
2022-04-19
Date Accepted
2022-03-29
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.
Citation
Nature Communications, 2022, 13 (1), pp. 2070 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Convergence SC Management