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

Jessica K Nelson1,2, May Zaw Thin1,2, Theodore Evan1

  • 1Adult Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

Nature Communications
|April 20, 2022
PubMed

Insights

Researchers identified USP25 as a key regulator in pancreatic cancer. Inhibiting USP25 effectively halts pancreatic ductal adenocarcinoma (PDAC) growth by targeting the HIF-1α pathway, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Deubiquitylating enzymes (DUBs) are crucial for protein degradation and emerging cancer therapeutics.
  • The therapeutic role of DUBs in pancreatic ductal adenocarcinoma (PDAC) remains largely unexplored.
  • PDAC is characterized by a hypoxic microenvironment impacting tumor biology.

Purpose of the Study:

  • To investigate the therapeutic potential of DUBs in PDAC.
  • To identify novel DUB targets regulating PDAC growth and survival.
  • To elucidate the molecular mechanisms underlying DUB function in PDAC.

Main Methods:

  • Developed a DUB discovery pipeline integrating activity-based proteomics.
  • Conducted loss-of-function genetic screens in patient-derived PDAC organoids and murine models.
  • Utilized genetic and pharmacological inhibition strategies for target validation.

Main Results:

  • Identified USP25 as a critical regulator of PDAC growth and maintenance.
  • Demonstrated potent inhibition of PDAC organoid growth and xenograft regression upon USP25 inhibition.
  • Showed USP25 deubiquitinates and stabilizes HIF-1α, impacting glycolysis and cell death in hypoxic PDAC cores.

Conclusions:

  • The USP25/HIF-1α axis is essential for metabolic reprogramming and survival in PDAC.
  • USP25 inhibition represents a promising therapeutic strategy for PDAC, targeting tumor-specific vulnerabilities.
  • Targeting USP25 offers a potential approach to exploit the hypoxic tumor microenvironment in PDAC.

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