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Lactate dehydrogenase A silencing in IDH mutant gliomas
Open accessAbstract
BACKGROUND: Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1α degradation and, by doing so, may have unexpected metabolic effects. METHODS: We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1α target genes in IDH mutant ((mt)) and IDH wild-type ((wt)) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas. RESULTS: We found that HIF1α-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDH(mt) gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDH(mt) derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDH(wt)), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDH(mt) glioblastomas. CONCLUSION: To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDH(mt) gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis.
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“It was demonstrated that brown adipocytes possess a unique capacity to sequester extracellular succinate, which serves to increase UCP1 activity as a consequence of elevated mtROS160.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [160]
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“a portion of the succinate that accumulates during ischemia and inflammation is released from the cell into the extracellular environment through poorly defined processes. This occurs following IR injury158,159, inflammation10, or cold exposure160.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [160]
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Cites
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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
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IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
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Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
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Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy
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IDH mutation in glioma: molecular mechanisms and potential therapeutic targets
Han, S., Liu, Y., Cai, S. J., Qian, M., Ding, J., Larion, M., Gilbert, M. R., & Yang, C. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0814-x · Cited by 701
The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor
Valvona, C. J., Fillmore, H. L., Nunn, P. B., & Pilkington, G. J. (2015) · Brain Pathology · doi:10.1111/bpa.12299 · Cited by 570
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398
Miroshnikova, Y. A., Mouw, J. K., Barnes, J. M., Pickup, M. W., Lakins, J. N., Kim, Y., Lobo, K. A., Persson, A. I., Reis, G. F., McKnight, T. R., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3429 · Cited by 390
Metadata
- Authors
- Chesnelong, C., Chaumeil, M. M., Blough, M. D., Al-Najjar, M., Stechishin, O. D., Chan, J. A., Pieper, R. O., Ronen, S. M., Weiss, S., Luchman, H. A., & Cairncross, J. G.
- Affiliations
- Foothills Medical Centre (CA)
- Corresponding author
- Cairncross, J. Gregory
- ORCID
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-12-22
- Volume
- 16
- Issue
- 5
- Pages
- 686-695
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- PMC
- PMC3984548
- OpenAlex
- W2101246344
- Cited by
- 210
- References
- 39
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 16 · 2023: 13 · 2022: 19 · 2021: 33 · 2020: 22 · 2019: 16 · 2018: 20 · 2017: 12 · 2016: 9 · 2015: 12 · 2014: 11
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuro-Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA172845)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- LDHA, IDH mutation, isocitrate dehydrogenase, glioma, brain tumor stem cells, hypoxia-inducible factor-1α, 2-hydroxyglutarate, DNA methylation, promoter methylation, glycolysis, glioblastoma, Warburg effect, cancer metabolism
- MeSH terms
- Lactate Dehydrogenase 5, Animals, Glioblastoma, Glioma, Humans, Isocitrate Dehydrogenase, Isoenzymes, L-Lactate Dehydrogenase, Mutation, Gene Expression Regulation, Neoplastic, DNA Methylation, Brain Stem Neoplasms, Gene Silencing, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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