Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism.
Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism.
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microRNA-137的表观遗传沉默增强ASCT2表达和肿瘤谷氨酰胺代谢
DOI：
10.1038/oncsis.2017.59
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发表时间：
2017-07-10
期刊：
影响因子：
6.2
通讯作者：
Qing G
中科院分区：
文献类型：
--
作者：
Dong J;Xiao D;Zhao Z;Ren P;Li C;Hu Y;Shi J;Su H;Wang L;Liu H;Li B;Gao P;Qing G
肿瘤细胞必须激活特定的转运蛋白以满足其增加的谷氨酰胺代谢需求。相对于其他谷氨酰胺转运蛋白，ASC家族转运蛋白2（ASCT 2，也称为SLC 1A 5）在广泛的人类癌症中显著升高，以协调代谢重编程和恶性转化。因此，了解肿瘤细胞频繁上调这种转运蛋白的分子机制对于开发转运蛋白靶向治疗的潜在策略至关重要。将计算机模拟算法与系统性实验筛选相结合，我们在本文中鉴定了肿瘤抑制microRNA，miR-137，作为靶向ASCT 2和癌细胞谷氨酰胺代谢的重要调节剂。代谢分析显示，miR-137去阻遏与ASCT 2失活类似，显著抑制谷氨酰胺消耗和TCA循环回补。从机制上讲，甲基CpG结合蛋白2（MeCP 2）和DNA甲基转移酶（DNMT）合作促进miR-137启动子的主动甲基化并抑制其转录，反过来重新激活ASCT 2表达和谷氨酰胺代谢。此外，在来自多种癌症类型的肿瘤标本中，miR-137和ASCT 2之间的表达呈负相关，并且异位ASCT 2表达显著挽救了miR-137对肿瘤发生的抑制。因此，这些发现阐明了先前未报道的人类癌症中ASCT 2失调的机制，并将ASCT 2确定为miR-137的关键下游效应子，揭示了DNA甲基化，microRNA和肿瘤代谢之间的分子联系。
Tumor cells must activate specific transporters to meet their increased glutamine metabolic demands. Relative to other glutamine transporters, the ASC family transporter 2 (ASCT2, also called SLC1A5) is profoundly elevated in a wide spectrum of human cancers to coordinate metabolic reprogramming and malignant transformation. Understanding the molecular mechanisms whereby tumor cells frequently upregulate this transporter is therefore vital to develop potential strategies for transporter-targeted therapies. Combining in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor microRNA, miR-137, as an essential regulator that targets ASCT2 and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and inhibit its transcription, conversely reactivating ASCT2 expression and glutamine metabolism. Moreover, expression between miR-137 and ASCT2 is inversely correlated in tumor specimens from multiple cancer types, and ectopic ASCT2 expression markedly rescued miR-137 suppression of tumorigenesis. These findings thus elucidate a previously unreported mechanism responsible for ASCT2 deregulation in human cancers and identify ASCT2 as a critical downstream effector of miR-137, revealing a molecular link between DNA methylation, microRNA and tumor metabolism.
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影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
21.3
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
通讯作者：
Goessling W
影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
ATF4 和 N-Myc 通过 ASCT2 激活协调 MYCN 扩增的神经母细胞瘤细胞中的谷氨酰胺代谢
影响因子：
7.3
作者：
Ren, Ping;Yue, Ming;Qing, Guoliang
通讯作者：
Qing, Guoliang
影响因子：
8.8
作者：
Neault, Mathieu;Mallette, Frederick A.;Richard, Stephane
通讯作者：
Richard, Stephane