Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Zeyad D Nassar; Chui Yan Mah; Jonas Dehairs; Ingrid JG Burvenich; Swati Irani; Margaret M Centenera; Madison Helm; Raj K Shrestha; Max Moldovan; Anthony S Don; Jeff Holst; Andrew M Scott; Lisa G Horvath; David J Lynn; Luke A Selth; Andrew J Hoy; Johannes V Swinnen; Lisa M Butler

doi:10.7554/eLife.54166

eLife (Jul 2020)

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Zeyad D Nassar,
Chui Yan Mah,
Jonas Dehairs,
Ingrid JG Burvenich,
Swati Irani,
Margaret M Centenera,
Madison Helm,
Raj K Shrestha,
Max Moldovan,
Anthony S Don,
Jeff Holst,
Andrew M Scott,
Lisa G Horvath,
David J Lynn,
Luke A Selth,
Andrew J Hoy,
Johannes V Swinnen,
Lisa M Butler

Affiliations

Zeyad D Nassar: ORCiD; University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Chui Yan Mah: ORCiD; University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Jonas Dehairs: KU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
Ingrid JG Burvenich: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, Australia
Swati Irani: University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Margaret M Centenera: University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Madison Helm: University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Raj K Shrestha: Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia
Max Moldovan: South Australian Health and Medical Research Institute, Adelaide, Australia
Anthony S Don: NHMRC Clinical Trials Centre, and Centenary Institute, The University of Sydney, Camperdown, Australia
Jeff Holst: Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
Andrew M Scott: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, Australia
Lisa G Horvath: Garvan Institute of Medical Research, NSW 2010; University of Sydney, NSW 2006; and University of New South Wales, Darlinghurst, Australia
David J Lynn: South Australian Health and Medical Research Institute, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, Australia
Luke A Selth: University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, Australia
Andrew J Hoy: Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
Johannes V Swinnen: KU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
Lisa M Butler: ORCiD; University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia

DOI: https://doi.org/10.7554/eLife.54166
Journal volume & issue: Vol. 9

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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