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 Rabinowitz, Maria Hatzoglou, Daniel J. Murphy, Russell Jones, Song Wu, Geoffrey Girnun, Wei Xing Zong

Research output: Contribution to journalArticle

51 Citations (Scopus)

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
Pages (from-to)1068-1077
Number of pages10
JournalCell Metabolism
Volume22
Issue number6
DOIs
Publication statusPublished - 2015 Jan 1

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Glutamate-Ammonia Ligase
Glutamine
Thymine DNA Glycosylase
Glutamic Acid
Glutaminase
Neoplasms
Ammonia
Heterografts
Cell Survival
Up-Regulation
Nucleotides
Cell Proliferation
Amino Acids
DNA
Growth

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Bott, Alex J. ; Peng, I-Chen ; Fan, Yongjun ; Faubert, Brandon ; Zhao, Lu ; Li, Jinyu ; Neidler, Sarah ; Sun, Yu ; Jaber, Nadia ; Krokowski, Dawid ; Lu, Wenyun ; Pan, Ji An ; Powers, Scott ; Rabinowitz, Joshua ; Hatzoglou, Maria ; Murphy, Daniel J. ; Jones, Russell ; Wu, Song ; Girnun, Geoffrey ; Zong, Wei Xing. / Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. In: Cell Metabolism. 2015 ; Vol. 22, No. 6. pp. 1068-1077.
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Bott, AJ, Peng, I-C, Fan, Y, Faubert, B, Zhao, L, Li, J, Neidler, S, Sun, Y, Jaber, N, Krokowski, D, Lu, W, Pan, JA, Powers, S, Rabinowitz, J, Hatzoglou, M, Murphy, DJ, Jones, R, Wu, S, Girnun, G & Zong, WX 2015, 'Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation', Cell Metabolism, vol. 22, no. 6, pp. 1068-1077. https://doi.org/10.1016/j.cmet.2015.09.025

Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. / Bott, Alex J.; Peng, I-Chen; Fan, Yongjun; Faubert, Brandon; Zhao, Lu; Li, Jinyu; Neidler, Sarah; Sun, Yu; Jaber, Nadia; Krokowski, Dawid; Lu, Wenyun; Pan, Ji An; Powers, Scott; Rabinowitz, Joshua; Hatzoglou, Maria; Murphy, Daniel J.; Jones, Russell; Wu, Song; Girnun, Geoffrey; Zong, Wei Xing.

In: Cell Metabolism, Vol. 22, No. 6, 01.01.2015, p. 1068-1077.

Research output: Contribution to journalArticle

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AU - Bott, Alex J.

AU - Peng, I-Chen

AU - Fan, Yongjun

AU - Faubert, Brandon

AU - Zhao, Lu

AU - Li, Jinyu

AU - Neidler, Sarah

AU - Sun, Yu

AU - Jaber, Nadia

AU - Krokowski, Dawid

AU - Lu, Wenyun

AU - Pan, Ji An

AU - Powers, Scott

AU - Rabinowitz, Joshua

AU - Hatzoglou, Maria

AU - Murphy, Daniel J.

AU - Jones, Russell

AU - Wu, Song

AU - Girnun, Geoffrey

AU - Zong, Wei Xing

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AB - 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.

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