title: 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.
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: German
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Haejin
authors.initials: H
authors.lastname: Yoon
authors.affiliation: 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.
authors.forename: Rushdia Z
authors.initials: RZ
authors.lastname: Yusuf
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Murphy
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Laurent
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: F Kyle
authors.initials: FK
authors.lastname: Satterstrom
authors.affiliation: 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.
authors.forename: Jlenia
authors.initials: J
authors.lastname: Guarnerio
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elma
authors.initials: E
authors.lastname: Zaganjor
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Santos
authors.affiliation: 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.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: 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.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
authors.affiliation: Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marcia_haigis@hms.harvard.edu.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D011392:Proline / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D040681:Structural Homology, Protein; D016019:Survival Analysis
chemical_list: D005227:Fatty Acids; D034741:RNA, Small Interfering; D011392:Proline; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase