1. PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.
- Author
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German NJ, Yoon H, Yusuf RZ, Murphy JP, Finley LW, Laurent G, Haas W, Satterstrom FK, Guarnerio J, Zaganjor E, Santos D, Pandolfi PP, Beck AH, Gygi SP, Scadden DT, Kaelin WG Jr, and Haigis MC
- Subjects
- Acetyl-CoA Carboxylase antagonists & inhibitors, Acetyl-CoA Carboxylase chemistry, Acetyl-CoA Carboxylase genetics, Amino Acid Sequence, Animals, Cell Line, Tumor, HEK293 Cells, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases chemistry, Hypoxia-Inducible Factor-Proline Dioxygenases genetics, K562 Cells, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Metabolic Networks and Pathways genetics, Mice, Mice, Inbred NOD, Models, Molecular, Neoplasm Transplantation, Oxidation-Reduction, Proline chemistry, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Structural Homology, Protein, Survival Analysis, Acetyl-CoA Carboxylase metabolism, Fatty Acids metabolism, Gene Expression Regulation, Neoplastic, Hypoxia-Inducible Factor-Proline Dioxygenases metabolism, Leukemia, Myeloid, Acute metabolism, Proline metabolism
- Abstract
While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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