Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation

Bott, A. J. et al. (2015) Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation. Cell Metabolism, 22(6), pp. 1068-1077. (doi: 10.1016/j.cmet.2015.09.025) (PMID:26603296) (PMCID:PMC4670565)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Neidler, Ms Sarah and Murphy, Professor Daniel
Authors: 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., and Zong, W.-X.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Metabolism
Publisher:Elsevier (Cell Press)
ISSN:1550-4131
ISSN (Online):1932-7420
Published Online:23 October 2015
Copyright Holders:Copyright © 2016 Elsevier (Cell Press)
First Published:First published in Cell Metabolism 22(6):1068-1077
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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