NRF2 regulates serine biosynthesis in non-small cell lung cancer
By G. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, J. Sudderth, Zeping Hu, David Wu, Hao Tang, Yang Xie, J. Asara, K. Huffman and 4 more. Nature Genetics, 2015
674 citations recorded by the source corpus.
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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/2800b1f76a9c65e8df8c9f703869e9547c3c64a9
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Citations in the corpus
- Nrf2, the Master Regulator of Anti-Oxidative Responses (2017, background): “Nrf2 induces the expression of enzymes of the pentose phosphate pathway [65,125], nucleotide biosynthesis [65], amino acid metabolism [57,126,127], and NADPH synthesis [128,129].”
- Transcriptional Regulation by Nrf2 (2017, background): “In human lung cancer cells, NRF2 regulates serine biosynthesis via activating transcription factor 4 (ATF4) and phosphoglycerate dehydrogenase (PHGDH) to support GSH and nucleotide production and coordinately activates the pentose phosphate pathway (PPP) to supply ribose for nucleic acid biosynthesi”
- Oxidative Stress in Cancer (2020, background): “Its upregulation in cancer cells can increase serine biosynthesis through its ability to positively control ATF4-mediated induction of phosphoglycerate dehydrogenase, phosphohydroxythreonine aminotransferase, phosphoserine phosphatase, and SHMT2 that support GSH and nucleotide synthesis (DeNicola et”
- NRF2, a Transcription Factor for Stress Response and Beyond (2020, background): “NRF2 activates the transcription of ATF4, which has been linked to amino acid metabolism and resistance to oxidative stress [88,99].”
- Targeting Metabolism for Cancer Therapy (2017, background): “, 2011) or a consequence of oncogenic signaling, including NRF2 and ATF4 signaling (DeNicola et al., 2015), or hypoxia responses (Samanta et al.”
- ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, background): “Also, the antioxidant transcription factor Nrf2 can regulate the expression of key one-carbon metabolism enzymes, including 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase 1 and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in human non-small cell lung cancer (NSCLC) cells, sup”