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Cell. 2019 Aug 8;178(4):807-819.e21. doi: 10.1016/j.cell.2019.07.031.

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Computational Biology, University of Lausanne, 1005 Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), 1005 Lausanne, Switzerland.
3
Microchemistry and Proteomics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Integrated Genomics Operation, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Antitumor Assessment Core and Molecular Pharmacology Department, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Oncode Institute, Tumor Biology and Immunology division, the Netherlands Cancer Institute, 1006 BE, Amsterdam, the Netherlands.
7
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA.
8
Microchemistry and Proteomics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: wendelh@mskcc.org.

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.

KEYWORDS:

EGFR; FN3K; KEAP1; NRF2; de-glycation; fructosamine; glucose; glycation; hepatocellular carcinoma; redox

PMID:
31398338
PMCID:
PMC6693658
[Available on 2020-08-08]
DOI:
10.1016/j.cell.2019.07.031

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