PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2
Open accessAbstract
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 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.
“PHD3 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.55–57”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [55]
ACC2 is hydroxylated by PHD3, and hydroxylation promotes ACC2 activity in nutrient abundance.
“ACC2 is also hydroxylated by the dioxygenase prolyl hydroxylase 3 (PHD3).55 Hydroxylation promotes ACC2 activity in nutrient abundance.”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [55]
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- Authors
- 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.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Haigis, Marcia C.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 63
- Issue
- 6
- Pages
- 1006-1020
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5040345
- OpenAlex
- W2519842257
- Cited by
- 156
- References
- 55
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 11 · 2023: 23 · 2022: 17 · 2021: 16 · 2020: 25 · 2019: 13 · 2018: 16 · 2017: 11 · 2016: 2
- FWCI
- 5.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IslandScholar (University of Prince Edward Island) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R35CA210068)
- National Institute of General Medical Sciences (T32GM007306)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103295, P60DK020541, T32DK007260)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PHD3, fatty acid oxidation, acetyl-CoA carboxylase 2, proline hydroxylation, cancer metabolism, acute myeloid leukemia, fuel switching, tumor cell proliferation, metabolic vulnerability
- MeSH terms
- Acetyl-CoA Carboxylase, Amino Acid Sequence, Animals, Fatty Acids, Humans, Hydroxylation, Male, Models, Molecular, Neoplasm Transplantation, Oxidation-Reduction, Proline, Signal Transduction, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Survival Analysis, Mice, Inbred NOD, K562 Cells, RNA, Small Interfering, Structural Homology, Protein, Cell Line, Tumor, Mice, Metabolic Networks and Pathways, HEK293 Cells, Hypoxia-Inducible Factor-Proline Dioxygenases
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