MYC-driven inhibition of the glutamate-cysteine ligase promotes glutathione depletion in liver cancer

EMBO Rep. 2017 Apr;18(4):569-585. doi: 10.15252/embr.201643068. Epub 2017 Feb 20.


How MYC reprograms metabolism in primary tumors remains poorly understood. Using integrated gene expression and metabolite profiling, we identify six pathways that are coordinately deregulated in primary MYC-driven liver tumors: glutathione metabolism; glycine, serine, and threonine metabolism; aminoacyl-tRNA biosynthesis; cysteine and methionine metabolism; ABC transporters; and mineral absorption. We then focus our attention on glutathione (GSH) and glutathione disulfide (GSSG), as they are markedly decreased in MYC-driven tumors. We find that fewer glutamine-derived carbons are incorporated into GSH in tumor tissue relative to non-tumor tissue. Expression of GCLC, the rate-limiting enzyme of GSH synthesis, is attenuated by the MYC-induced microRNA miR-18a. Inhibition of miR-18a in vivo leads to increased GCLC protein expression and GSH abundance in tumor tissue. Finally, MYC-driven liver tumors exhibit increased sensitivity to acute oxidative stress. In summary, MYC-dependent attenuation of GCLC by miR-18a contributes to GSH depletion in vivo, and low GSH corresponds with increased sensitivity to oxidative stress in tumors. Our results identify new metabolic pathways deregulated in primary MYC tumors and implicate a role for MYC in regulating a major antioxidant pathway downstream of glutamine.

Keywords: MYC; cancer; glutathione; metabolism; miRNA.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cluster Analysis
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glutamate-Cysteine Ligase / antagonists & inhibitors*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutamine / metabolism
  • Glutathione / metabolism*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Metabolic Networks and Pathways / genetics
  • Metabolome
  • Metabolomics / methods
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • Oxidative Stress
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference


  • MIRN18 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Glutamine
  • GCLC protein, human
  • Glutamate-Cysteine Ligase
  • Glutathione