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
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 CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 1 December 2015 |
| Date Deposited: | 06 Mar 2018 17:41 |
| Last Modified: | 05 Nov 2020 20:53 |
| PMCID: | PMC4670565 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36177 |
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