TY - JOUR T1 - DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis JF - bioRxiv DO - 10.1101/865626 SP - 865626 AU - Zeyad D. Nassar AU - Chui Yan Mah AU - Jonas Dehairs AU - Ingrid J.G. Burvenich AU - Swati Irani AU - Margaret M. Centenera AU - Raj K. Shrestha AU - Max Moldovan AU - Anthony S. Don AU - Andrew M. Scott AU - Lisa G. Horvath AU - David J. Lynn AU - Luke A. Selth AU - Andrew J. Hoy AU - Johannes V. Swinnen AU - Lisa M. Butler Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/12/06/865626.abstract N2 - Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in 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, which encodes 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 in PCa cells selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation in vivo. Mechanistically, targeting of DECR1 caused cellular accumulation of linoleic acid, enhanced mitochondrial oxidative stress and lipid peroxidation, and ferroptosis. These findings implicate PUFA oxidation via DECR1 as a previously unexplored facet of FAO that promotes survival of PCa cells. ER -