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

Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation.

Author information

1
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
2
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA; Department of Life Sciences, National Cheng Kung University, Tainan City 701, Taiwan.
3
Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
4
Department of Applied Mathematics, Stony Brook University, Stony Brook, New York 11794, USA.
5
Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
6
Institute of Cancer Sciences, University of Glasgow, and the CRUK Beatson Institute, Glasgow G61 1BD, UK.
7
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
8
Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ 08544, USA.
9
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA. Electronic address: weixing.zong@pharmacy.rutgers.edu.

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.

PMID:
26603296
PMCID:
PMC4670565
DOI:
10.1016/j.cmet.2015.09.025
[Indexed for MEDLINE]
Free PMC Article

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