IDH1, a CHOP and C/EBPβ-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis

Cancer Lett. 2015 Sep 1;365(2):201-10. doi: 10.1016/j.canlet.2015.05.027. Epub 2015 Jun 3.


Isocitrate dehydrogenase1 (IDH1) is of great importance in cell metabolism and energy conversion. However, alterations in IDH1 in response to stress and excise-regulated mechanisms are not well described. Here we investigated gene expression profiles under ER stress in melanoma cells and found that IDH1 was dramatically increased with ER stress induced by tunicamycin. Elevated IDH1 subsequently sensitized human melanoma cells to hypoxia-induced apoptosis and promoted HIF-1α degradation. In addition, we revealed that CHOP and C/EBPβ were involved in hypoxia-induced apoptosis via transcriptional regulation of IDH1 expression. Our data indicate that IDH1, regulated by CHOP and C/EBPβ in response to ER stress treatment, inhibits survival of melanoma cells under hypoxia and promotes HIF-1α degradation. Therefore, we propose that IDH1 may serve as a valuable target for melanoma therapy.

Keywords: Apoptosis; CHOP; ER stress; HIF-1α; IDH1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Binding Sites / genetics
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • Cell Hypoxia
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Isocitrate Dehydrogenase / biosynthesis
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism*
  • Melanoma / pathology*
  • Neoplasm Invasiveness / genetics
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Transcription Factor CHOP / genetics
  • Tunicamycin / pharmacology
  • Up-Regulation


  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • DDIT3 protein, human
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Tunicamycin
  • Transcription Factor CHOP
  • Isocitrate Dehydrogenase
  • IDH1 protein, human