NRF2 regulates serine biosynthesis in non-small cell lung cancer

Gina M DeNicola; Pei-Hsuan Chen; Edouard Mullarky; Jessica A Sudderth; Zeping Hu; David Wu; Hao Tang; Yang Xie; John M Asara; Kenneth E Huffman; Ignacio I Wistuba; John D Minna; Ralph J DeBerardinis; Lewis C Cantley

doi:10.1038/ng.3421

NRF2 regulates serine biosynthesis in non-small cell lung cancer

Nat Genet. 2015 Dec;47(12):1475-81. doi: 10.1038/ng.3421. Epub 2015 Oct 19.

Authors

Affiliations

¹ Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
² Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
³ Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
⁴ Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
⁵ Hamon Center for Therapeutic Oncology, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
⁶ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

PMID: 26482881
PMCID: PMC4721512
DOI: 10.1038/ng.3421

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism*
Adenocarcinoma / mortality
Adenocarcinoma / secondary
Animals
Apoptosis
Biomarkers, Tumor / genetics*
Biomarkers, Tumor / metabolism
Blotting, Western
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / secondary
Cell Proliferation
Gene Expression Regulation, Neoplastic*
Humans
Immunoenzyme Techniques
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Mice
NF-E2-Related Factor 2 / antagonists & inhibitors
NF-E2-Related Factor 2 / genetics*
NF-E2-Related Factor 2 / metabolism
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Serine / biosynthesis*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
NF-E2-Related Factor 2
NFE2L2 protein, human
RNA, Messenger
RNA, Small Interfering
Serine

Abstract

Publication types

MeSH terms

Substances

Grants and funding