MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
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DOI：
10.1172/jci71180
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发表时间：
2014-01-01
影响因子：
15.9
通讯作者：
Ambs, Stefan
中科院分区：
文献类型：
--
作者：
Terunuma, Atsushi;Putluri, Nagireddy;Ambs, Stefan
最近，癌细胞的代谢图谱被认为是开发治疗和识别癌症生物标记物的一种很有前途的工具。在这里，我们描述了人类乳腺肿瘤的代谢特征，并使用非靶向发现方法和关键代谢物的验证发现了这些肿瘤的内在代谢物特征。肿瘤和人乳腺癌细胞株中的肿瘤代谢产物2-羟基戊二酸(2HG)水平较高。我们发现乳腺癌中2HG水平升高和MYC途径激活之间存在关联，并通过人乳腺上皮和乳腺癌细胞中MYC的过度表达和基因敲除进一步证实了这种关系。进一步的分析显示，在2HG高的肿瘤中，DNA甲基化在全球范围内增加，并发现了一种肿瘤亚型，具有高组织2HG和独特的DNA甲基化模式，与不良预后相关，在非裔美国人患者中发生率较高。这种亚型的肿瘤具有干细胞样的转录特征，并倾向于过度表达谷氨酰胺酶，提示乳腺癌中谷氨酰胺和2HG代谢之间存在功能关系。因此，在2HG异常聚集的细胞中，13C标记的谷氨酰胺被结合到2HG中，而药物和siRNA介导的谷氨酰胺酶抑制降低了2HG的水平。我们的发现表明2HG是乳腺癌的候选肿瘤代谢物，与MYC激活和预后不良有关。
Metabolic profiling of cancer cells has recently been established as a promising tool for the development of therapies and identification of cancer biomarkers. Here we characterized the metabolomic profile of human breast tumors and uncovered intrinsic metabolite signatures in these tumors using an untargeted discovery approach and validation of key metabolites. The oncometabolite 2-hydroxyglutarate (2HG) accumulated at high levels in a subset of tumors and human breast cancer cell lines. We discovered an association between increased 2HG levels and MYC pathway activation in breast cancer, and further corroborated this relationship using MYC overexpression and knockdown in human mammary epithelial and breast cancer cells. Further analyses revealed globally increased DNA methylation in 2HG-high tumors and identified a tumor subtype with high tissue 2HG and a distinct DNA methylation pattern that was associated with poor prognosis and occurred with higher frequency in African-American patients. Tumors of this subtype had a stem cell-like transcriptional signature and tended to overexpress glutaminase, suggestive of a functional relationship between glutamine and 2HG metabolism in breast cancer. Accordingly, 13C-labeled glutamine was incorporated into 2HG in cells with aberrant 2HG accumulation, whereas pharmacologic and siRNA-mediated glutaminase inhibition reduced 2HG levels. Our findings implicate 2HG as a candidate breast cancer oncometabolite associated with MYC activation and poor prognosis.