Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

Cell Metab. 2015 Dec 1;22(6):1068-77. doi: 10.1016/j.cmet.2015.09.025. Epub 2015 Oct 23.

Abstract

c-Myc is known to promote glutamine usage by upregulating glutaminase (GLS), which converts glutamine to glutamate that is catabolized in the TCA cycle. Here we report that in a number of human and murine cells and cancers, Myc induces elevated expression of glutamate-ammonia ligase (GLUL), also termed glutamine synthetase (GS), which catalyzes the de novo synthesis of glutamine from glutamate and ammonia. This is through upregulation of a Myc transcriptional target thymine DNA glycosylase (TDG), which promotes active demethylation of the GS promoter and its increased expression. Elevated expression of GS promotes cell survival under glutamine limitation, while silencing of GS decreases cell proliferation and xenograft tumor growth. Upon GS overexpression, increased glutamine enhances nucleotide synthesis and amino acid transport. These results demonstrate an unexpected role of Myc in inducing glutamine synthesis and suggest a molecular connection between DNA demethylation and glutamine metabolism in Myc-driven cancers.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA / metabolism
  • DNA Methylation
  • Female
  • Glutamate-Ammonia Ligase / antagonists & inhibitors
  • Glutamate-Ammonia Ligase / genetics
  • Glutamate-Ammonia Ligase / metabolism*
  • Glutamic Acid / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Nucleotides / biosynthesis
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • Nucleotides
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Glutamic Acid
  • DNA
  • DNA (Cytosine-5-)-Methyltransferases
  • Glutamate-Ammonia Ligase