2. Academic Validation
  3. Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth

Lipid-metabolism-focused CRISPR screens identify enzymes of the mevalonate pathway as essential for prostate cancer growth

  • Cell Rep. 2025 Apr 22;44(4):115470. doi: 10.1016/j.celrep.2025.115470.
Gio Fidelito 1,  Izabela Todorovski 2,  Leonie Cluse 2,  Stephin J Vervoort 3,  Renea A Taylor 4,  Matthew J Watt 5
Affiliations

Affiliations

  • 1 Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 2 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 3 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • 4 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Melbourne Urological Research Alliance (MURAL), Monash University, Clayton, VIC 3168, Australia; Cabrini Institute, Cabrini Health, Malvern, VIC 3144, Australia. Electronic address: renea.taylor@monash.edu.
  • 5 Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: matt.watt@unimelb.edu.au.
PMID: 40146774 DOI: 10.1016/j.celrep.2025.115470
Abstract

Dysregulated lipid metabolism plays an important role in prostate Cancer, although the understanding of the essential regulatory processes in tumorigenesis is incomplete. We employ a CRISPR-Cas9 screen using a custom human lipid metabolism knockout library to identify essential genes for prostate Cancer survival. Screening in three prostate Cancer cell lines reveals 63 shared dependencies, with enrichment in terpenoid backbone synthesis and N-glycan biosynthesis. Independent knockout of key genes of the mevalonate pathway reduces cell proliferation. Further investigation focuses on NUS1, a subunit of cis-prenyltransferase required for dolichol synthesis. NUS1 knockout decreases tumor growth in vivo and viability in patient-derived xenograft (PDX)-derived organoids. Mechanistic studies reveal that loss of NUS1 promotes oxidative stress, lipid peroxidation and Ferroptosis sensitivity, endoplasmic reticulum (ER) stress, and G1 cell-cycle arrest, and it dampens Androgen Receptor (AR) signaling, collectively leading to growth arrest. This study highlights the critical role of the mevalonate-dolichol-N-glycan biosynthesis pathway, particularly NUS1, in prostate Cancer survival and growth.

Keywords

CP: Cancer; CP: Metabolism; CRISPR screen; cancer metabolism; lipid metabolism; prostate cancer.

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