Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus

Junsheng Fu, Zhaohui Xiong, Caizhi Huang, Jing Li, Wenjun Yang, Yuning Han, Chorlada Paiboonrungruan, Michael B. Major, Ke Neng Chen, Xiaozheng Kang, Xiaoxin Chen

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2/, Keap1/, K5Cre;Pkm2fl/fl;Keap1/, and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro. In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2high ESCC in humans.

Original languageEnglish
Pages (from-to)327-340
Number of pages14
JournalJournal of Biological Chemistry
Volume294
Issue number1
DOIs
StatePublished - Jan 4 2019
Externally publishedYes

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    Fu, J., Xiong, Z., Huang, C., Li, J., Yang, W., Han, Y., Paiboonrungruan, C., Major, M. B., Chen, K. N., Kang, X., & Chen, X. (2019). Hyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus. Journal of Biological Chemistry, 294(1), 327-340. https://doi.org/10.1074/jbc.RA118.005963