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

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 developed 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 identified USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition resulted in potent growth impairment in PDAC organoids, while normal pancreatic organoids were insensitive, and caused dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinated and stabilised the HIF-1a transcription factor. PDAC is characterised by a severely hypoxic microenvironment, and USP25 depletion abrogated HIF-1a transcriptional activity and impaired glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1a axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.

ORGANISM(S): Mus musculus

PROVIDER: GSE166077 | GEO | 2022/03/01

REPOSITORIES: GEO

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USP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma

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