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

Natalie J. German; Haejin Yoon; Rushdia Z. Yusuf; J. Patrick Murphy; Lydia W.S. Finley; Gaëlle Laurent; Wilhelm Haas; F. Kyle Satterstrom; Jlenia Guarnerio; Elma Zaganjor; Daniel Santos; Pier Paolo Pandolfi; Andrew H. Beck; Steven P. Gygi; David T. Scadden; William G. Kaelin; Marcia C. Haigis

doi:10.1016/j.molcel.2016.08.014

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

Natalie J. German, Haejin Yoon, Rushdia Z. Yusuf, J. Patrick Murphy, Lydia W.S. Finley, Gaëlle Laurent, Wilhelm Haas, F. Kyle Satterstrom, Jlenia Guarnerio, Elma Zaganjor, Daniel Santos, Pier Paolo Pandolfi, Andrew H. Beck, Steven P. Gygi, David T. Scadden, William G. Kaelin, Marcia C. Haigis

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Résumé

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.

Langue d'origine	English
Pages (de-à)	1006-1020
Nombre de pages	15
Journal	Molecular Cell
Volume	63
Numéro de publication	6
DOI	https://doi.org/10.1016/j.molcel.2016.08.014
Statut de publication	Published - sept. 15 2016
Publié à l'externe	Oui

Note bibliographique

Funding Information:
We thank David Sykes, Giovanni Roti, Ninib Baryawno, and Qing Zhang for assay advice. We thank Peppi Karppinen at the University of Oulu for recombinant PHD3. We thank the Stable Isotope and Metabolomics Core Facility at the Albert Einstein College of Medicine (NIH/NCI grant P60DK020541) for acylcarnitine measurements. N.J.G. is supported by the National Science Foundation Graduate Research Fellowship Grant 1000087636 and NIH Training Grant T32 GM007306. P.P.P., A.H.B., S.P.G., D.T.S., and W.G.K are supported by NIH grants. W.G.K. is a Howard Hughes Medical Institute investigator. M.C.H. is supported by NIH grant DK103295 from the NIDDK, the Ludwig Center at Harvard, Glenn Foundation for Medical Research, and American Cancer Society New Scholar Award. This work is funded in part by the Alexander and Margaret Stewart Trust Grant.

Publisher Copyright:
© 2016 Elsevier Inc.

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1016/j.molcel.2016.08.014

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German, N. J., Yoon, H., Yusuf, R. Z., Murphy, J. P., Finley, L. W. S., Laurent, G., Haas, W., Satterstrom, F. K., Guarnerio, J., Zaganjor, E., Santos, D., Pandolfi, P. P., Beck, A. H., Gygi, S. P., Scadden, D. T., Kaelin, W. G., & Haigis, M. C. (2016). PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2. Molecular Cell, 63(6), 1006-1020. https://doi.org/10.1016/j.molcel.2016.08.014

German, NJ, Yoon, H, Yusuf, RZ, Murphy, JP, Finley, LWS, Laurent, G, Haas, W, Satterstrom, FK, Guarnerio, J, Zaganjor, E, Santos, D, Pandolfi, PP, Beck, AH, Gygi, SP, Scadden, DT, Kaelin, WG & Haigis, MC 2016, 'PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2', Molecular Cell, vol. 63, n° 6, pp. 1006-1020. https://doi.org/10.1016/j.molcel.2016.08.014

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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.",

author = "German, {Natalie J.} and Haejin Yoon and Yusuf, {Rushdia Z.} and Murphy, {J. Patrick} and Finley, {Lydia W.S.} and Ga{\"e}lle Laurent and Wilhelm Haas and Satterstrom, {F. Kyle} and Jlenia Guarnerio and Elma Zaganjor and Daniel Santos and Pandolfi, {Pier Paolo} and Beck, {Andrew H.} and Gygi, {Steven P.} and Scadden, {David T.} and Kaelin, {William G.} and Haigis, {Marcia C.}",

note = "Funding Information: We thank David Sykes, Giovanni Roti, Ninib Baryawno, and Qing Zhang for assay advice. We thank Peppi Karppinen at the University of Oulu for recombinant PHD3. We thank the Stable Isotope and Metabolomics Core Facility at the Albert Einstein College of Medicine (NIH/NCI grant P60DK020541) for acylcarnitine measurements. N.J.G. is supported by the National Science Foundation Graduate Research Fellowship Grant 1000087636 and NIH Training Grant T32 GM007306. P.P.P., A.H.B., S.P.G., D.T.S., and W.G.K are supported by NIH grants. W.G.K. is a Howard Hughes Medical Institute investigator. M.C.H. is supported by NIH grant DK103295 from the NIDDK, the Ludwig Center at Harvard, Glenn Foundation for Medical Research, and American Cancer Society New Scholar Award. This work is funded in part by the Alexander and Margaret Stewart Trust Grant. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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doi = "10.1016/j.molcel.2016.08.014",

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AU - German, Natalie J.

AU - Yoon, Haejin

AU - Yusuf, Rushdia Z.

AU - Murphy, J. Patrick

AU - Finley, Lydia W.S.

AU - Laurent, Gaëlle

AU - Haas, Wilhelm

AU - Satterstrom, F. Kyle

AU - Guarnerio, Jlenia

AU - Zaganjor, Elma

AU - Santos, Daniel

AU - Pandolfi, Pier Paolo

AU - Beck, Andrew H.

AU - Gygi, Steven P.

AU - Scadden, David T.

AU - Kaelin, William G.

AU - Haigis, Marcia C.

N1 - Funding Information: We thank David Sykes, Giovanni Roti, Ninib Baryawno, and Qing Zhang for assay advice. We thank Peppi Karppinen at the University of Oulu for recombinant PHD3. We thank the Stable Isotope and Metabolomics Core Facility at the Albert Einstein College of Medicine (NIH/NCI grant P60DK020541) for acylcarnitine measurements. N.J.G. is supported by the National Science Foundation Graduate Research Fellowship Grant 1000087636 and NIH Training Grant T32 GM007306. P.P.P., A.H.B., S.P.G., D.T.S., and W.G.K are supported by NIH grants. W.G.K. is a Howard Hughes Medical Institute investigator. M.C.H. is supported by NIH grant DK103295 from the NIDDK, the Ludwig Center at Harvard, Glenn Foundation for Medical Research, and American Cancer Society New Scholar Award. This work is funded in part by the Alexander and Margaret Stewart Trust Grant. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/9/15

Y1 - 2016/9/15

N2 - 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.

AB - 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.

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

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODD de l’ONU

Accès au document

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