TY - JOUR
T1 - Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents
AU - Wang, Pu
AU - Wu, Jing
AU - Ma, Shenghong
AU - Zhang, Lei
AU - Yao, Jun
AU - Hoadley, Katherine A.
AU - Wilkerson, Matthew D.
AU - Perou, Charles M.
AU - Guan, Kun Liang
AU - Ye, Dan
AU - Xiong, Yue
N1 - Funding Information:
We thank the members of the Fudan MCB lab and Y.X.’s lab at UNC for discussion and support throughout this study. Lingchao Chen in Fudan and Dale Ramsden at UNC provided for many valuable suggestions and discussions. This work was supported by the 973 Program (no. 2012CB910303, no. 2012CB910101, no. 2011CB910600, no. 2009CB918401), the NSFC grant (no. 81522033 to D.Y.), and International Postdoctoral Exchange Fellowship Program 2013 of Chinese Postdoctoral Council (to P.W.). J.W. is supported by K12CA120780-04 and a grant from UNC Neurosurgery Research Fund. This work was supported by NIH grants (CA163834 to Y.X., CA196878 to K.-L.G.), and Samuel Waxman Foundation (to Y.X.).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/12/22
Y1 - 2015/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84952871257&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.11.029
DO - 10.1016/j.celrep.2015.11.029
M3 - Article
C2 - 26686626
AN - SCOPUS:84952871257
SN - 2211-1247
VL - 13
SP - 2353
EP - 2361
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -