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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere54166
Number of pages34
JournaleLife
Volume9
DOIs
Publication statusPublished - 20 Jul 2020

Bibliographical note

Copyright Nassar et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Keywords

  • androgen
  • cancer biology
  • ferroptosis
  • human
  • lipid metabolism
  • mouse
  • prostate cancer

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    Nassar, Z. D., Mah, C. Y., Dehairs, J., Burvenich, I. J., Irani, S., Centenera, M. M., Helm, M., Shrestha, R. K., Moldovan, M., Don, A. S., Holst, J., Scott, A. M., Horvath, L. G., Lynn, D. J., Selth, L. A., Hoy, A. J., Swinnen, J. V., & Butler, L. M. (2020). 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