Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation.
Oncogenic Myc Induces Expression of Glutamine Synthetase through Promoter Demethylation.
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DOI：
10.1016/j.cmet.2015.09.025
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发表时间：
2015-12-01
期刊：
影响因子：
29
通讯作者：
Zong WX
中科院分区：
文献类型：
--
作者：
Bott AJ;Peng IC;Fan Y;Faubert B;Zhao L;Li J;Neidler S;Sun Y;Jaber N;Krokowski D;Lu W;Pan JA;Powers S;Rabinowitz J;Hatzoglou M;Murphy DJ;Jones R;Wu S;Girnun G;Zong WX
众所周知，c-Myc通过上调谷氨酰胺酶(GLS)来促进谷氨酰胺的使用，谷氨酰胺酶将谷氨酰胺转化为谷氨酸，谷氨酸在TCA循环中分解。在此，我们报道了在许多人类和小鼠细胞和癌症中，Myc诱导谷氨酸氨连接酶(GLUL)，也称为谷氨酰胺合成酶(GS)的表达增加，该酶催化谷氨酸和氨从头合成谷氨酰胺。这是通过上调Myc转录靶标胸腺嘧啶DNA糖基酶(TDG)，促进GS启动子的主动去甲基化及其表达增加。在谷氨酰胺限制下，GS的高表达促进了细胞的存活，而GS的沉默则降低了细胞的增殖和移植瘤的生长。当GS过表达时，增加的谷氨酰胺促进核苷酸合成和氨基酸运输。这些结果表明，Myc在诱导谷氨酰胺合成方面发挥了意想不到的作用，并表明在Myc驱动的癌症中，DNA去甲基化与谷氨酰胺代谢之间存在新的分子联系。
c-Myc is known to promotes glutamine usage by up-regulating 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 novel molecular connection between DNA demethylation and glutamine metabolism in Myc-driven cancers.