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Mol Cell. 2016 Sep 15;63(6):1006-20. doi: 10.1016/j.molcel.2016.08.014.

PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.

Author information

1
Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
2
Stem Cell and Regenerative Biology Department, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
3
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
6
Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marcia_haigis@hms.harvard.edu.

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.

PMID:
27635760
PMCID:
PMC5040345
DOI:
10.1016/j.molcel.2016.08.014
[Indexed for MEDLINE]
Free PMC Article

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