NRF2 regulates serine biosynthesis in non-small cell lung cancer.
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.
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Gina M
GM
DeNicola
Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Pei-Hsuan
PH
Chen
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Edouard
E
Mullarky
Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Jessica A
JA
Sudderth
Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Zeping
Z
Hu
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
David
D
Wu
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Hao
H
Tang
Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Yang
Y
Xie
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
John M
JM
Asara
Hamon Center for Therapeutic Oncology, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Kenneth E
KE
Huffman
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Ignacio I
II
Wistuba
Hamon Center for Therapeutic Oncology, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
John D
JD
Minna
Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
Ralph J
RJ
DeBerardinis
Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Lewis C
LC
Cantley
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012694:Serine