Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
- University of Adelaide, Australia
- KU Leuven, Belgium
- Olivia Newton-John Cancer Research Institute, Australia
- South Australian Health and Medical Research Institute, Australia
- University of Sydney, Australia
- University of New South Wales, Australia
- Chris O'Brien Lifehouse, Australia
Abstract
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Article and author information
Author details
Funding
National Health and Medical Research Council (Early Career Fellowship,1138648)
- Zeyad D Nassar
KU Leuven (Project Grants C16/15/073 and C32/17/052)
- Johannes V Swinnen
Australian Research Council (Future Fellowship,FT130101004)
- Lisa M Butler
Cancer Council South Australia (Beat Cancer Fellowship,PRF1117)
- Lisa M Butler
Movember Foundation (Revolutionary Team Award,MRTA3)
- Lisa M Butler
National Health and Medical Research Council (Project Grant,1121057)
- Luke A Selth
National Health and Medical Research Council (Project Grant,1100626)
- Anthony S Don
National Health and Medical Research Council (Fellowship,1084178)
- Andrew M Scott
Prostate Cancer Foundation of Australia (Young Investigator Award,YI 1417)
- Zeyad D Nassar
Cure Cancer Australia Foundation (Project Grant,1164798)
- Zeyad D Nassar
EMBL Australia (Group Leader Award)
- David J Lynn
University of Sydney (Robinson Fellowship)
- Andrew J Hoy
Fonds Wetenschappelijk Onderzoek (Project Grants G.0841.15 and G.0C22.19N)
- Johannes V Swinnen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were approved by the Austin Health Animal Ethics Committee (approval number A2015/05311), Heidelberg, Australia, and the University of Adelaide Animal Ethics Committee (approval number M-2019-037), and were carried out in accordance with the recommendations of the National Health and Medical Research Council of Australia.
Human subjects: Fresh and archival prostate tissue specimens were collected from men undergoing robotic radical prostatectomy at St. Andrew's Hospital (Adelaide, South Australia) with written informed consent through the Australian Prostate Cancer BioResource. Ethical Approval was provided by the Human Research Ethics Committees of the University of Adelaide (H-2012-016) and St Andrew's Hospital.
Copyright
© 2020, Nassar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
eLife 9:e54166.
https://doi.org/10.7554/eLife.54166
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