TY - JOUR TI - Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis AU - Nassar, Zeyad D AU - Mah, Chui Yan AU - Dehairs, Jonas AU - Burvenich, Ingrid JG AU - Irani, Swati AU - Centenera, Margaret M AU - Helm, Madison AU - Shrestha, Raj K AU - Moldovan, Max AU - Don, Anthony S AU - Holst, Jeff AU - Scott, Andrew M AU - Horvath, Lisa G AU - Lynn, David J AU - Selth, Luke A AU - Hoy, Andrew J AU - Swinnen, Johannes V AU - Butler, Lisa M A2 - Sharifi, Nima A2 - Murphy, Maureen E VL - 9 PY - 2020 DA - 2020/07/20 SP - e54166 C1 - eLife 2020;9:e54166 DO - 10.7554/eLife.54166 UR - https://doi.org/10.7554/eLife.54166 AB - 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. KW - lipid metabolism KW - prostate cancer KW - ferroptosis KW - androgen JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -