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

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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

Zeyad D Nassar

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7779-2697
Chui Yan Mah

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8820-4037
Jonas Dehairs

Oncology, KU Leuven, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Ingrid JG Burvenich

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Swati Irani

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Margaret M Centenera

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Madison Helm

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Raj K Shrestha

Medicine, University of Adelaide, Adelaide, Australia

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The authors declare that no competing interests exist.
Max Moldovan

Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Anthony S Don

Charles Perkins Centre, University of Sydney, Sydney, Australia

Competing interests
The authors declare that no competing interests exist.
Jeff Holst

School of Medical Sciences, University of New South Wales, Sydney, Australia

Competing interests
The authors declare that no competing interests exist.
Andrew M Scott

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Lisa G Horvath

Oncology, Chris O'Brien Lifehouse, Sydney, Australia

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The authors declare that no competing interests exist.
David J Lynn

Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Luke A Selth

Medicine, University of Adelaide, Adelaide, Australia

Competing interests
The authors declare that no competing interests exist.
Andrew J Hoy

Charles Perkins Centre, University of Sydney, Sydney, Australia

Competing interests
The authors declare that no competing interests exist.
Johannes V Swinnen

Oncology, KU Leuven, Leuven, Belgium

Competing interests
The authors declare that no competing interests exist.
Lisa M Butler

Medicine, University of Adelaide, Adelaide, Australia

For correspondence
lisa.butler@adelaide.edu.au

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2698-3220

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.

Reviewing Editor

Nima Sharifi, Cleveland Clinic, United States

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.

Version history

Received: December 4, 2019
Accepted: July 16, 2020
Accepted Manuscript published: July 20, 2020 (version 1)
Version of Record published: July 28, 2020 (version 2)

Copyright

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.