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

FEBS Letters

article

Kancharana Bala Bhaskara Rao¹  Kumar Katragunta³  Uma Maheswara Sarma³  Nishant Jain¹ 

[1]Department of Applied Biology, CSIR-Indian Institute of Chemical Technology

[2]Academy of Scientific and Innovative Research (AcSIR)

[3]Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology

关键词: cell cycle;    D-2HG;    FOXM1;    G2/M;    IDH1;    IDH2;   

DOI  :  10.1002/1873-3468.13500

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown