Abundance of d-2-hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1-expressing cells

FEBS Lett. 2019 Aug;593(16):2177-2193. doi: 10.1002/1873-3468.13500. Epub 2019 Jul 4.

Abstract

Isocitrate dehydrogenases (IDHs) are metabolic enzymes that are mutated in several cancers, resulting in overproduction of d-2-hydroxyglutarate (D-2HG). However, the signalling pathways and factors that regulate mutant IDHs or their metabolites remain elusive. Here, we report that in synchronized cells and cells treated with anti-mitotic agents, wild-type and mutant IDH proteins are induced maximally in G2/M. Moreover, mutant IDH1-expressing cells arrested in G2/M harbour high D2HG levels. Genetic or pharmacological perturbation of Forkhead box protein M1 (FOXM1) abrogates the levels of IDH1 mRNA, protein and D2HG in G2/M. Conversely, overexpression of FOXM1 or hyperactive FOXM1 activates the IDH1 promoter and increases the abundance of its protein levels. In summary, our results show that in G2/M, higher D2HG levels are dependent on FOXM1-mediated transcription of IDH1.

Keywords: D-2HG; FOXM1; G2/M; IDH1; IDH2; cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Antimitotic Agents / pharmacology
  • Cell Line, Tumor
  • Forkhead Box Protein M1 / genetics*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockout Techniques
  • Glutarates / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism*
  • Mutation*
  • Promoter Regions, Genetic / drug effects

Substances

  • Antimitotic Agents
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Glutarates
  • alpha-hydroxyglutarate
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human