NRF2 regulates serine biosynthesis in non-small cell lung cancer.
NRF2 regulates serine biosynthesis in non-small cell lung cancer.
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DOI：
10.1038/ng.3421
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发表时间：
2015-12
期刊：
影响因子：
30.8
通讯作者：
Cantley LC
中科院分区：
文献类型：
--
作者：
DeNicola GM;Chen PH;Mullarky E;Sudderth JA;Hu Z;Wu D;Tang H;Xie Y;Asara JM;Huffman KE;Wistuba II;Minna JD;DeBerardinis RJ;Cantley LC
肿瘤对细胞的快速生长和增殖具有高能量和合成代谢的需求，而丝氨酸生物合成途径最近被确定为这些过程的代谢中间体的重要来源。我们整合了大量非小细胞肺癌（NSCLC）细胞系的代谢追踪和转录谱分析，以表征NSCLC中丝氨酸/甘氨酸生物合成途径的活性和调控。本研究表明，该通路的活性是高度异质性的，并受NRF2调控，NRF2是一种在非小细胞肺癌中经常失调的转录因子。我们发现NRF2通过ATF4控制关键丝氨酸/甘氨酸生物合成酶基因phgdh、psat1和shmt2的表达，以支持谷胱甘肽和核苷酸的产生。此外，我们发现这些基因的表达导致人类非小细胞肺癌预后不良。因此，很大一部分人类非小细胞肺癌激活nrf2依赖的转录程序，该程序调节丝氨酸和甘氨酸的代谢，并与临床侵袭性有关。
Tumors have high energetic and anabolic needs for rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes,. We integrated metabolic tracing and transcriptional profiling of a large panel of non–small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. We found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genesPHGDH,PSAT1andSHMT2via ATF4 to support glutathione and nucleotide production. Moreover, we show that expression of these genes confers poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.