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

Author:

Nassar Zeyad D12ORCID,Mah Chui Yan12ORCID,Dehairs Jonas3,Burvenich Ingrid JG4,Irani Swati12,Centenera Margaret M12,Helm Madison12,Shrestha Raj K5,Moldovan Max2,Don Anthony S6,Holst Jeff7,Scott Andrew M4,Horvath Lisa G8,Lynn David J29,Selth Luke A159,Hoy Andrew J10,Swinnen Johannes V3,Butler Lisa M12ORCID

Affiliation:

1. University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia

2. South Australian Health and Medical Research Institute, Adelaide, Australia

3. KU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium

4. Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, Australia

5. Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia

6. NHMRC Clinical Trials Centre, and Centenary Institute, The University of Sydney, Camperdown, Australia

7. Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia

8. Garvan Institute of Medical Research, NSW 2010; University of Sydney, NSW 2006; and University of New South Wales, Darlinghurst, Australia

9. College of Medicine and Public Health, Flinders University, Bedford Park, Australia

10. Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, 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.

Funder

National Health and Medical Research Council

Prostate Cancer Foundation of Australia

Cure Cancer Australia Foundation

EMBL Australia

University of Sydney

Fonds Wetenschappelijk Onderzoek

KU Leuven

Australian Research Council

Cancer Council South Australia

Movember Foundation

Freemasons Foundation Centre for Men's Health, University of Adelaide

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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