Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

Alex J. Bott, I. Chen Peng, Yongjun Fan, Brandon Faubert, Lu Zhao, Jinyu Li, Sarah Neidler, Yu Sun, Nadia Jaber, Dawid Krokowski, Wenyun Lu, Ji An Pan, Scott Powers, Joshua D. Rabinowitz, Maria Hatzoglou, Daniel J. Murphy, Russell Jones, Song Wu, Geoffrey Girnun, Wei Xing Zong

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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.

Original languageEnglish (US)
Pages (from-to)1068-1077
Number of pages10
JournalCell Metabolism
Volume22
Issue number6
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Bott, A. J., Peng, I. C., Fan, Y., Faubert, B., Zhao, L., Li, J., Neidler, S., Sun, Y., Jaber, N., Krokowski, D., Lu, W., Pan, J. A., Powers, S., Rabinowitz, J. D., Hatzoglou, M., Murphy, D. J., Jones, R., Wu, S., Girnun, G., & Zong, W. X. (2015). Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. Cell Metabolism, 22(6), 1068-1077. https://doi.org/10.1016/j.cmet.2015.09.025