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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.7554/eLife.54166
Journal or Publication Title: eLife
Volume: 9
Date: 2020
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.7554/eLife.54166
ISSN: 2050-084X
Date Deposited: 04 Jan 2021 00:02
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.

Creators:
Creators
Email
Nassar, Zeyad D
UNSPECIFIED
Mah, Chui Yan
UNSPECIFIED
Dehairs, Jonas
UNSPECIFIED
Burvenich, Ingrid JG
UNSPECIFIED
Irani, Swati
UNSPECIFIED
Centenera, Margaret M
UNSPECIFIED
Helm, Madison
UNSPECIFIED
Shrestha, Raj K
UNSPECIFIED
Moldovan, Max
UNSPECIFIED
Don, Anthony S
UNSPECIFIED
Holst, Jeff
UNSPECIFIED
Scott, Andrew M
UNSPECIFIED
Horvath, Lisa G
UNSPECIFIED
Lynn, David J
UNSPECIFIED
Selth, Luke A
UNSPECIFIED
Hoy, Andrew J
UNSPECIFIED
Swinnen, Johannes V
UNSPECIFIED
Butler, Lisa M
UNSPECIFIED
Last Modified: 04 Jan 2021 00:02
URI: https://eprints.centenary.org.au/id/eprint/823

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