Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents
Open accessAbstract
Chemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients.
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High levels of succinate or 2-HG inhibit α-KGDDs, including PHDs, TET DNA demethylases, and JMJDs.
“High levels of succinate or 2-HG inhibit α-KGDDs. These include the PHDs, the TET DNA demethylases, and the JMJDs154-156”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [156]
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References 31 · Cited by 206
- Authors
- Wang, P., Wu, J., Ma, S., Zhang, L., Yao, J., Hoadley, K. A., Wilkerson, M. D., Perou, C. M., Guan, K.-L., Ye, D., & Xiong, Y.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Corresponding author
- Guan, Kun-Liang
- Ye, Dan
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 13
- Issue
- 11
- Pages
- 2353-2361
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4694633
- OpenAlex
- W2195565943
- Cited by
- 206
- References
- 31
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 18 · 2023: 20 · 2022: 12 · 2021: 34 · 2020: 27 · 2019: 17 · 2018: 23 · 2017: 14 · 2016: 8
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- UNC Libraries
- Funders
- Samuel Waxman Cancer Research Foundation
- National Natural Science Foundation of China (973 Program, 2012CB910101, 81522033)
- National Institutes of Health (2k12ca120780-16, K12CA120780)
- National Key Research and Development Program of China (2012CB910303)
- National Cancer Institute (CA163834, R35CA196878, K12-CA120780, R01CA108941, R01CA132809, R01CA163834, CA196878)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- D-2-hydroxyglutarate, IDH mutation, ALKBH2, ALKBH3, DNA repair, alkylating agents, procarbazine, lomustine, vincristine, glioma, alpha-ketoglutarate, DNA damage, oncometabolites, chemosensitization
- MeSH terms
- AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase, AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase, Alkylating Agents, Busulfan, DNA Damage, DNA Repair, Glutarates, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mutation, Protein Binding, RNA Interference, RNA, Small Interfering, DNA Repair Enzymes, Cell Line, Tumor, Dioxygenases
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