The oncogenic action of NRF2 depends on de-glycation by fructosamine-3-kinase Journal Article

Authors: Sanghvi, V. R.; Leibold, J.; Mina, M.; Mohan, P.; Berishaj, M.; Li, Z.; Miele, M. M.; Lailler, N.; Zhao, C.; de Stanchina, E.; Viale, A.; Akkari, L.; Lowe, S. W.; Ciriello, G.; Hendrickson, R. C.; Wendel, H. G.
Article Title: The oncogenic action of NRF2 depends on de-glycation by fructosamine-3-kinase
Abstract: The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)—a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer. Fructosamine-3-kinase promotes hepatocellular carcinoma by mediating deglycation of NRF2, a protein modification process previously understudied for cellular proteins. © 2019 Elsevier Inc.
Keywords: hepatocellular carcinoma; glucose; egfr; fructosamine; redox; nrf2; keap1; glycation; de-glycation; fn3k
Journal Title: Cell
Volume: 178
Issue: 4
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2019-08-08
Start Page: 807
End Page: 819.e21
Language: English
DOI: 10.1016/j.cell.2019.07.031
PUBMED: 31398338
PROVIDER: scopus
PMCID: PMC6693658
Notes: Article -- Source: Scopus
Citation Impact
MSK Authors
  1. Agnes Viale
    231 Viale
  2. Hans Guido Wendel
    79 Wendel
  3. Scott W Lowe
    192 Lowe
  4. Chunying Zhao
    6 Zhao
  5. Viraj Sanghvi
    10 Sanghvi
  6. Nathalie Josette Lailler
    10 Lailler
  7. Prathibha Mohan
    11 Mohan
  8. Matthew M Miele
    6 Miele
  9. Josef Leibold
    12 Leibold
  10. Zhuoning Li
    3 Li