title: Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Bott
authors.affiliation: 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.
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Peng
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Faubert
authors.affiliation: Department of Applied Mathematics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, and the CRUK Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Neidler
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jaber
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ 08544, USA.
authors.forename: Wenyun
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Pan
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ 08544, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rabinowitz
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, and the CRUK Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Murphy
authors.affiliation: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Russell
authors.initials: R
authors.lastname: Jones
authors.affiliation: Department of Applied Mathematics, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Girnun
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA. Electronic address: weixing.zong@pharmacy.rutgers.edu.
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009711:Nucleotides / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D009711:Nucleotides; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018698:Glutamic Acid; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D005974:Glutamate-Ammonia Ligase