199 Citations (Scopus)

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1475-1481
Number of pages7
JournalNature Genetics
Volume47
Issue number12
DOIs
StatePublished - Dec 1 2015

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Non-Small Cell Lung Carcinoma
Serine
Glycine
Biosynthetic Pathways
Glutathione
Transcription Factors
Nucleotides
Cell Proliferation
Gene Expression
Cell Line
Enzymes
Growth
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

DeNicola, G. M., Chen, P. H., Mullarky, E., Sudderth, J. A., Hu, Z., Wu, D., ... Cantley, L. C. (2015). NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nature Genetics, 47(12), 1475-1481. https://doi.org/10.1038/ng.3421

NRF2 regulates serine biosynthesis in non-small cell lung cancer. / DeNicola, Gina M.; Chen, Pei Hsuan; Mullarky, Edouard; Sudderth, Jessica A.; Hu, Zeping; Wu, David; Tang, Hao; Xie, Yang; Asara, John M.; Huffman, Kenneth E.; Wistuba, Ignacio I.; Minna, John D.; DeBerardinis, Ralph J.; Cantley, Lewis C.

In: Nature Genetics, Vol. 47, No. 12, 01.12.2015, p. 1475-1481.

Research output: Contribution to journalArticle

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 2015, 'NRF2 regulates serine biosynthesis in non-small cell lung cancer', Nature Genetics, vol. 47, no. 12, pp. 1475-1481. https://doi.org/10.1038/ng.3421
DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nature Genetics. 2015 Dec 1;47(12):1475-1481. https://doi.org/10.1038/ng.3421
DeNicola, Gina M. ; Chen, Pei Hsuan ; Mullarky, Edouard ; Sudderth, Jessica A. ; Hu, Zeping ; Wu, David ; Tang, Hao ; Xie, Yang ; Asara, John M. ; Huffman, Kenneth E. ; Wistuba, Ignacio I. ; Minna, John D. ; DeBerardinis, Ralph J. ; Cantley, Lewis C. / NRF2 regulates serine biosynthesis in non-small cell lung cancer. In: Nature Genetics. 2015 ; Vol. 47, No. 12. pp. 1475-1481.
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AU - Wu, David

AU - Tang, Hao

AU - Xie, Yang

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AU - Minna, John D.

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