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

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.

The diversity and breadth of cancer cell fatty acid metabolism

“…Selective knockdown of these enzymes impacts growth and tumorigenicity of prostate cancer cells, but not non-malignant lines, coincident with an accumulation of cellular PUFAs, resulting in increased lipid peroxidation and induction of ferroptosis [ 300 , 301 ]. Androgenic regulation of these enzymes [ 299 , 300 ] further emphasizes their potential importance to prostate tumorigenesis. These effects, however, appear to be cancer type-specific, with DECR1 shown to be decreased in mouse models of breast cancer and in clinical breast tumors compared to normal mammary gland [ 302 , 303 ], and ectopic expression of DECR1 in HER2/neu-transformed breast cancer cells reducing tumorigenesis—an effect linked to reduced de novo lipogenesis [ 303 ].…”

“…This can occur enzymatically via the action of lipoxygenases (ALOX1-6), which catalyze deoxygenation of PUFAs to form lipid hydroperoxides, or as discovered in a lentiviral screen of genes that suppress ferroptosis, the catalytic subunit of the phosphorylase kinase complex, PHKG2 [298] which, when inhibited, prevents the formation of lipid hydroperoxides. Interrogation of clinical tissue-derived datasets has revealed that two of the enzymes involved in the auxiliary pathway of PUFA betaoxidation, ECI2 and the rate-limiting enzyme DECR1, are overexpressed in human prostate cancers [299][300][301] and associated with poorer overall patient survival [299,300]. Selective knockdown of these enzymes impacts growth and tumorigenicity of prostate cancer cells, but not non-malignant lines, coincident with an accumulation of cellular PUFAs, resulting in increased lipid peroxidation and induction of ferroptosis [300,301].…”

“…Interrogation of clinical tissue-derived datasets has revealed that two of the enzymes involved in the auxiliary pathway of PUFA betaoxidation, ECI2 and the rate-limiting enzyme DECR1, are overexpressed in human prostate cancers [299][300][301] and associated with poorer overall patient survival [299,300]. Selective knockdown of these enzymes impacts growth and tumorigenicity of prostate cancer cells, but not non-malignant lines, coincident with an accumulation of cellular PUFAs, resulting in increased lipid peroxidation and induction of ferroptosis [300,301]. Androgenic regulation of these enzymes [299,300] further emphasizes their potential importance to prostate tumorigenesis.…”

Metabolic Regulation of Ferroptosis in Cancer

“…These genes were upregulated in mesenchymal-type gastric cancer cells leading to their sensitization to ferroptosis. In contrast, prostate cancers exhibit enhanced fatty acid oxidation (FAO) and increased expression of 2,4 dienoyl-CoA reductase 1 (DECR1), a rate-limiting enzyme in β-oxidation of PUFA, in malignant prostate tissues compared to nonmalignant tissues [ 93 ]. Targeting of DECR1 not only resulted in a disruption of PUFA β-oxidation but accumulation of PUFAs in phospholipids that caused cells to become susceptible to ferroptosis.…”

Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

“…Due to the unrestricted multiplicative nature of cancer cells, tumors exhibit different metabolic statues from normal tissue, thus provide a possible way to identify tumors through the difference in metabolism. Recent studies have proven that some metabolisms, such as citrate and choline metabolism, are closely related to PCa (3). Studies have also shown that based on the variance in metabolites, such as increased urea cycle metabolites, PCa can be characterized (4).…”