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NRF2 regulates serine biosynthesis in non–small cell lung cancer

Nature Genetics volume 47, pages 1475–1481 (2015)Cite this article

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An Erratum to this article was published on 29 March 2016

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Abstract

Tumors have high energetic and anabolic needs for rapid cell growth and proliferation1, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes2,3. 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.

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Figure 1: Serine biosynthesis activity in lung cancer.
Figure 2: NRF2 regulates serine biosynthesis.
Figure 3: NRF2 regulates the expression of serine/glycine biosynthesis genes through ATF4.
Figure 4: PHGDH-derived serine supports the transsulfuration and folate cycles.
Figure 5: Activation of the serine biosynthesis pathway promotes tumorigenesis in NSCLC.
Figure 6: Model of the regulation of serine/glycine biosynthesis by NRF2.

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  • 15 February 2016

    In the version of this article initially published, the colors of the lines in the key in the top right corner of Figure 5h were incorrect. The line labeled "High" should be red and the line labeled "Low" should be blue. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank G. Poulogiannis for bioinformatics advice and H. Abbasi, C. Klimko and M. Yuan for technical support with mass spectrometry experiments. This work was supported by US National Institutes of Health grants P01 CA117969 and R01 GM041890 (L.C.C.), R01 CA157996-01 (R.J.D.), 5R01 CA152301 (Y.X.) and P50 CA70907 (J.D.M., I.I.W., Y.X. and K.E.H.) and by Cancer Prevention Research Institute of Texas (CPRIT) funding to J.D.M., Y.X., I.I.W. and K.E.H. (RP110708 and RP120732) and R.J.D. (RP130272). P.-H.C. was supported by a grant from the Welch Foundation to R.J.D. (I-1733). The mass spectrometry work was partially supported by US National Institutes of Health grants 5P30 CA006516 and 5 P01 CA120964 (J.M.A.). G.M.D. was the Malcolm A.S. Moore Hope Funds for Cancer Research Fellow and is supported by the PanCAN/AACR Pathway to Leadership grant.

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Author notes

  1. Pei-Hsuan Chen and Edouard Mullarky: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Weill Cornell Medical College, New York, New York, USA

    Gina M DeNicola, Edouard Mullarky, David Wu & Lewis C Cantley

  2. Children's Medical Center Research Institute, University of Texas–Southwestern Medical Center, Dallas, Texas, USA

    Pei-Hsuan Chen, Jessica A Sudderth, Zeping Hu & Ralph J DeBerardinis

  3. Department of Clinical Sciences, Quantitative Biomedical Research Center, University of Texas–Southwestern Medical Center, Dallas, Texas, USA

    Hao Tang & Yang Xie

  4. Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    John M Asara

  5. Hamon Center for Therapeutic Oncology, University of Texas–Southwestern Medical Center, Dallas, Texas, USA

    Kenneth E Huffman & John D Minna

  6. Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Ignacio I Wistuba

Authors
  1. Gina M DeNicola
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Contributions

G.M.D., R.J.D. and L.C.C. designed the study. G.M.D. and E.M. performed molecular biology experiments. G.M.D., P.-H.C., E.M., J.A.S., Z.H. and J.M.A. performed metabolomics and isotope labeling and analyzed the data. D.W. performed xenograft experiments. H.T. and Y.X. performed bioinformatics analysis. K.E.H., I.I.W. and J.D.M. contributed highly annotated lung cancer cell lines. G.M.D., E.M. and L.C.C. wrote the manuscript. All authors commented on the manuscript.

Corresponding author

Correspondence to Lewis C Cantley.

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Competing interests

L.C.C. owns equity in, receives compensation from and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways in cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival. R.J.D. is on the scientific advisory boards of Agios Pharmaceuticals and Peloton Therapeutics. Peloton Therapeutics is developing drugs to target altered molecular pathways in cancer, including altered metabolism.

Supplementary information

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Supplementary Figures 1–22, Supplementary Tables 2–5 and Supplementary Note. (PDF 6832 kb)

Supplementary Table 1

Gene expression correlations with [13C]serine and [13C]glycine labeling at 6 and 24 h. (XLSX 161 kb)

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DeNicola, G., Chen, PH., Mullarky, E. et al. NRF2 regulates serine biosynthesis in non–small cell lung cancer. Nat Genet 47, 1475–1481 (2015). https://doi.org/10.1038/ng.3421

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