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

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

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,Haigis MC

doi

10.1016/j.molcel.2016.08.014

subject

Has Abstract

pub_date

2016-09-15 00:00:00

pages

1006-20

issue

6

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(16)30428-2

journal_volume

63

pub_type

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