ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer

Abstract The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation novel AR targeting therapies, outcomes for metastatic disease remain dismal. There an urgent need to better understand androgen-regulated cellular processes more effectively target dependence cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark enhanced signaling in yet relationship between lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length phospholipids from patient-derived explants one most striking changes metabolism. Potent direct AR-mediated induction ELOVL acid elongase 5 (ELOVL5), enzyme that catalyzes elongation, was demonstrated cells, xenografts, clinical tumors. Assessment mRNA protein large-scale data sets revealed ELOVL5 predominant expressed upregulated compared with nonmalignant prostate. depletion markedly altered mitochondrial morphology function, leading excess generation reactive oxygen species resulting suppression cell proliferation, 3D growth, vivo tumor growth metastasis. Supplementation monounsaturated cis-vaccenic acid, product reversed oxidative stress associated proliferation migration effects knockdown. Collectively, these results identify elongation protumorigenic metabolic pathway androgen-regulated, critical metastasis, targetable via ELOVL5. Significance: This identifies phospholipid action