Journal
NATURE GENETICS
Volume 47, Issue 12, Pages 1475-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3421
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Funding
- US National Institutes of Health [P01 CA117969, R01 GM041890, R01 CA157996-01, 5R01 CA152301, P50 CA70907, 5P30 CA006516, 5 P01 CA120964]
- Cancer Prevention Research Institute of Texas (CPRIT) [RP110708, RP120732, RP130272]
- Welch Foundation [I-1733]
- PanCAN/AACR Pathway to Leadership grant
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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.
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