Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Open accessAbstract
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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PHGDH expression and increased serine biosynthesis are important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings.
“Serine is present in plasma and can be taken up by cells via amino acid transporters, yet PHGDH expression and increased serine biosynthesis have been shown to be important for supporting cancer cell proliferation and survival in both in vitro and in vivo settings (Locasale et al., 2011; Possemato et al., 2011).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Locasale et al., 2011
Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux.
“Functional PHGDH loss is toxic to tumor cells with PHGDH amplification or high serine biosynthetic flux (Locasale et al., 2011; Mattaini et al., 2015; Possemato et al., 2011; Zhang et al., 2017), and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Locasale et al., 2011
Increased PHGDH expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma.
“Increased PHGDH gene expression leads to greater production of serine from glucose and is associated with specific subsets of breast cancer, lung adenocarcinoma, and melanoma (Locasale et al., 2011; Possemato et al., 2011; Zhang et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Locasale et al., 2011
Increased PHGDH expression in some cancers can result from copy number gain of a region on chromosome 1p or from oncogenic signaling including NRF2 and ATF4 signaling or hypoxia responses.
“More recently, it was found that increased expression of the serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH) in some cancers can result from copy number gain of a region on chromosome 1p (Beroukhim et al., 2010; Locasale et al., 2011; Possemato et al., 2011) or a consequence of oncogenic signaling, including NRF2 and ATF4 signaling (DeNicola et al., 2015), or hypoxia responses (Sam”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Locasale et al., 2011
Many PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of PHGDH, but for some tumor models PHGDH expression is dispensable for growth.
“Similarly, many PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of the enzyme (Locasale et al., 2011; Mullarky et al., 2016; Pacold et al., 2016; Possemato et al., 2011; Wang et al., 2017; Zhang et al., 2017), but for some tumor models PHGDH expression can be dispensable for growth (Chen et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Locasale et al., 2011
Cancer cells may utilize as much as 50% of glucose-derived carbon in serine biosynthesis and subsequent catabolism.
“cancer cells may utilize as much as 50% of glucose-derived carbon in serine biosynthesis and its subsequent catabolism”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Locasale et al., 2011
PHGDH is frequently focally amplified in breast cancer and melanoma and is required for growth of PHGDH-amplified cells in vitro and in vivo.
“A rate-limiting serine biosynthesis enzyme, 3-phosphoglycerate dehydrogenase (PHGDH), is frequently focally amplified in breast cancer and melanoma and is required for the growth of PHGDH-amplified cells in vitro as well as in vivo”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Locasale et al., 2011
PHGDH amplification has been observed in breast cancer and melanoma.
“Amplification of PHGDH has been observed in breast cancer and melanoma (65), and increased PHGDH expression can promote both enhanced serine biosynthesis and the proliferation of cancer cells (65, 66).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [65]
Increased PHGDH expression can promote enhanced serine biosynthesis and the proliferation of cancer cells.
“Amplification of PHGDH has been observed in breast cancer and melanoma (65), and increased PHGDH expression can promote both enhanced serine biosynthesis and the proliferation of cancer cells (65, 66).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [65]
The region of chromosome 1p12 encoding PHGDH is amplified in a significant fraction of tumors.
“the region of chromosome 1p12 encoding PHGDH is amplified in a significant fraction of tumors”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Locasale et al., 2011
Over-expressing PHGDH was sufficient to promote anchorage independence in breast epithelial cells and to disturb cell polarity, phenotypes taken to be consistent with malignancy.
“over-expressing PHGDH was sufficient to promote anchorage independence in breast epithelial cells and to disturb cell polarity, phenotypes taken to be consistent with malignancy”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Locasale et al., 2011
Cell lines derived from tumors with PHGDH amplification tend to be highly dependent on PHGDH expression.
“cell lines derived from these tumors tend to be highly dependent on PHGDH expression”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Locasale et al., 2011
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- Authors
- Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., Sasaki, A. T., Anastasiou, D., Mullarky, E., Vokes, N. I., Sasaki, M., Beroukhim, R., Stephanopoulos, G., Ligon, A. H., Meyerson, M., Richardson, A. L., Chin, L., Wagner, G., Asara, J. M., Brugge, J. S., Cantley, L. C., & Vander Heiden, M. G.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Broad Institute (US)
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Locasale, Jason W
- Cantley, Lewis C
- ORCID
- Locasale, Jason W
- Lyssiotis, Costas A
- Mattaini, Katherine R
- Bass, Adam J
- Heffron, Gregory
- Metallo, Christian M
- Muranen, Taru
- Sasaki, Atsuo T
- Anastasiou, Dimitrios
- Vokes, Natalie I
- Sasaki, Mika
- Beroukhim, Rameen
- Stephanopoulos, Gregory
- Ligon, Azra H
- Meyerson, Matthew
- Richardson, Andrea L
- Wagner, Gerhard
- Asara, John M
- Brugge, Joan S
- Cantley, Lewis C
- Venue
- Nature Genetics
- Published
- 2011-07-31
- Volume
- 43
- Issue
- 9
- Pages
- 869-874
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3677549
- OpenAlex
- W2126524529
- Cited by
- 1,120
- References
- 36
- Citations by year
- 2026: 42 · 2025: 53 · 2024: 64 · 2023: 71 · 2022: 70 · 2021: 103 · 2020: 97 · 2019: 86 · 2018: 62 · 2017: 73 · 2016: 88 · 2015: 74 · 2014: 79 · 2013: 68 · 2012: 71
- FWCI
- 25.69
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Science Foundation
- Wellcome Trust
- National Institutes of Health
- National Cancer Institute (R01CA160458, P01CA120964, P30CA014051)
- National Institute of General Medical Sciences (R01GM056203)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- PHGDH, serine biosynthesis, glycine synthesis, cancer metabolism, carcinogenesis, melanoma, breast cancer, copy number gain, tumor cell proliferation, mammary epithelial cells, acinar morphogenesis
- MeSH terms
- Cell Transformation, Neoplastic, Glucose, Glycolysis, Humans, Neoplasms, Cell Proliferation, Phosphoglycerate Dehydrogenase
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