Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation

被引:212
作者
Bott, Alex J. [1 ]
Peng, I-Chen [1 ,10 ]
Fan, Yongjun [1 ]
Faubert, Brandon [4 ]
Zhao, Lu [2 ]
Li, Jinyu [3 ]
Neidler, Sarah [5 ,6 ]
Sun, Yu [1 ]
Jaber, Nadia [1 ]
Krokowski, Dawid [7 ]
Lu, Wenyun [8 ,9 ]
Pan, Ji-An [1 ]
Powers, Scott [3 ]
Rabinowitz, Joshua
Hatzoglou, Maria [7 ]
Murphy, Daniel J. [5 ,6 ]
Jones, Russell [4 ]
Wu, Song [2 ]
Girnun, Geoffrey [3 ]
Zong, Wei-Xing [1 ]
机构
[1] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA
[2] SUNY Stony Brook, Dept Appl Math, Stony Brook, NY 11794 USA
[3] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA
[4] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada
[5] Univ Glasgow, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland
[6] CRUK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland
[7] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA
[8] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA
[9] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA
[10] Natl Cheng Kung Univ, Dept Life Sci, Tainan 701, Taiwan
关键词
DNA METHYLATION; CELL BIOLOGY; METABOLISM; CANCER; MUSCLE; PROGRAM; PROTEIN; LEADS;
D O I
10.1016/j.cmet.2015.09.025
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1068 / 1077
页数:10
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