NRF2 regulates serine biosynthesis in non-small cell lung cancer

被引：592

作者：

DeNicola, Gina M. ^{[1
]}

Chen, Pei-Hsuan ^{[2
]}

Mullarky, Edouard ^{[1
]}

Sudderth, Jessica A. ^{[2
]}

Hu, Zeping ^{[2
]}

Wu, David ^{[1
]}

Tang, Hao ^{[3
]}

Xie, Yang ^{[3
]}

Asara, John M. ^{[4
]}

Huffman, Kenneth E. ^{[5
]}

Wistuba, Ignacio I. ^{[6
]}

Minna, John D. ^{[5
]}

DeBerardinis, Ralph J. ^{[2
]}

Cantley, Lewis C. ^{[1
]}

机构：

[1] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[2] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA

[4] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02215 USA

[5] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol, Dallas, TX 75390 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 12期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; KEAP1; MUTATIONS; GROWTH; ACTIVATION; CARCINOMA; GLUTAMINE; PATHWAY; GLUCOSE; PROTEIN; IMPAIR;

D O I：

10.1038/ng.3421

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Tumors have high energetic and anabolic needs for rapid cell growth and proliferation(1), and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes(2,3). 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 genes PHGDH, PSAT1 and SHMT2 via 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.

引用

页码：1475 / +

页数：9

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