Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

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., Hatzoglou, M., Murphy, D. J., Jones, R., Wu, S., Girnun, G., Zong, W. X. (December 2015) Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation. Cell Metab, 22 (6). pp. 1068-77. ISSN 1550-4131

URL: https://www.ncbi.nlm.nih.gov/pubmed/26603296
DOI: 10.1016/j.cmet.2015.09.025

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.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Line DNA/metabolism DNA (Cytosine-5-)-Methyltransferases/metabolism DNA Methylation Female Glutamate-Ammonia Ligase/antagonists & inhibitors/genetics/*metabolism Glutamic Acid/metabolism Humans Mice Mice, Nude Nucleotides/biosynthesis Promoter Regions, Genetic Proto-Oncogene Proteins c-myc/genetics/*metabolism RNA Interference RNA, Small Interfering/metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL labs > Powers lab
Depositing User: Matt Covey
Date: 1 December 2015
Date Deposited: 06 Mar 2018 17:41
Last Modified: 06 Mar 2018 17:41
PMCID: PMC4670565
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36177

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