Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents

Pu Wang; Jing Wu; Shenghong Ma; Lei Zhang; Jun Yao; Katherine A Hoadley; Matthew D Wilkerson; Charles M Perou; Kun-Liang Guan; Dan Ye; Yue Xiong

doi:10.1016/j.celrep.2015.11.029

Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents

Cell Rep. 2015 Dec 22;13(11):2353-2361. doi: 10.1016/j.celrep.2015.11.029. Epub 2015 Dec 10.

Authors

Pu Wang¹, Jing Wu², Shenghong Ma³, Lei Zhang⁴, Jun Yao⁴, Katherine A Hoadley⁵, Matthew D Wilkerson⁶, Charles M Perou⁵, Kun-Liang Guan⁷, Dan Ye⁸, Yue Xiong⁹

Affiliations

¹ Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China.
⁴ Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁵ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
⁸ Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China. Electronic address: yedan@fudan.edu.cn.
⁹ Molecular and Cell Biology Lab of Key Laboratory of Molecular Medicine of Ministry of Education and Institutes of Biomedical Sciences, Shanghai Medical College, College of Life Science, Fudan University, Shanghai 200032, China; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

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.

Publication types

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

MeSH terms

AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
Alkylating Agents / toxicity*
Busulfan / toxicity
Cell Line, Tumor
DNA Damage / drug effects*
DNA Repair / drug effects
DNA Repair Enzymes / antagonists & inhibitors
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism*
Dioxygenases / antagonists & inhibitors
Dioxygenases / genetics
Dioxygenases / metabolism
Glutarates / metabolism
Glutarates / pharmacology*
Humans
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism*
Ketoglutaric Acids / metabolism
Mutation
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism

Substances

Alkylating Agents
Glutarates
Ketoglutaric Acids
RNA, Small Interfering
alpha-hydroxyglutarate
Isocitrate Dehydrogenase
Dioxygenases
ALKBH3 protein, human
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
ALKBH2 protein, human
AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase
DNA Repair Enzymes
Busulfan

Abstract

Publication types

MeSH terms

Substances

Grants and funding