GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.
GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.
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DOI：
10.1158/0008-5472.can-16-2289
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Zhang S
中科院分区：
文献类型：
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作者：
Schnepp PM;Lee DD;Guldner IH;O'Tighearnaigh TK;Howe EN;Palakurthi B;Eckert KE;Toni TA;Ashfeld BL;Zhang S
氨基酸代谢改变对癌症进展的影响尚未完全了解。我们假设，在转移性进展过程中代谢转录组的变化对脑转移至关重要。在这里，我们报告了一个强大的影响，在这种情况下引起的谷氨酸脱羧酶1（GAD 1），GABA神经递质代谢途径的调节表观遗传上调。在基于细胞的培养和脑转移模型中，我们发现由脑微环境衍生的丛生素诱导的DNA甲基转移酶DNMT 1的下调导致脑转移肿瘤细胞中GAD 1启动子甲基化降低和随后的GAD 1表达上调。在一个系统中，动态可视化GAD 1介导的细胞代谢反应，我们监测肿瘤细胞中的胞质NADH：NAD+平衡。通过原代神经胶质细胞共培养减少转移细胞中的GAD 1消除了转移细胞利用细胞外谷氨酰胺的能力，导致NADH的胞质积累和氧化状态增加。类似地，GABA代谢途径的遗传或药理学破坏降低了体内脑转移的发生率。综上所述，我们的研究结果表明GAD 1表达的表观遗传变化如何改变脑转移微环境中的局部谷氨酸代谢，从而促进代谢适应，促进该环境中的转移生长。
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.