Fructosamine-3-kinase (FN3K) activity promotes oncogenesis in models of liver and lung cancer.

  • Major Finding: Fructosamine-3-kinase (FN3K) activity promotes oncogenesis in models of liver and lung cancer.

  • Mechanism: FN3K deglycates the oncogenic transcription factor NRF2, increasing its stability and activity.

  • Impact: Glycation's role in cancer should be further explored, and FN3K inhibitors may be worth pursuing.

Little is known about the effects of protein glycation, the nonenzymatic linkage of basic amino-acid residues to monosaccharides. Sanghvi and colleagues discovered a role for glycation of the oncogenic transcription factor NRF2, finding that the activity of the typically heavily glycated protein is dependent on deglycation by fructosamine-3-kinase (FN3K). In a mouse model, the development of MYC-driven hepatocellular carcinoma (HCC) was dependent on NRF2 activation. A pan-cancer genome-wide SELECT analysis revealed that NRF2 activation and EGFR mutations were mutually exclusive in treatment-naïve patients, indicating that their functions may overlap. In a genome-wide CRISPR screen, Fn3k emerged as a regulator of NRF2 activation. Two in silico analyses predicted that several residues in NRF2′s N- and C-terminal domains would be glycated, and an assay in an HCC cell line with mutant KEAP1 (which encodes a regulator of NRF2 that binds its N-terminal domain) detected glycated NRF2 upon FN3K knockdown. In liver and lung cancer cells with wild-type KEAP1, FNK3 loss impaired the induction and nuclear accumulation of NRF2 normally triggered by a chemical NRF2 stimulator, causing a decrease in the expression of NRF2 target proteins and increased sensitivity to oxidative stress. FN3K knockdown led to a substantial decrease in NRF2′s apparent stability in cells with wild-type KEAP1, but not in cells with mutant KEAP1; further, in KEAP1-mutant cells, glycation reduced NRF2′s activity. Analysis by mass spectrometry provided a detailed characterization and quanitification of NRF2 glycation in cancer cells and indicated that NRF2 glycation was dependent on glucose and sensitive to FN3K. In mouse models of lung and liver cancers, lack of FN3K prevented the oncogenic and drug resistance–promoting effects of NRF2. Demonstrating the potential broader relevance of these findings, mass spectrometry on cell lysates identified 110 proteins whose glycation levels were significantly altered by FN3K deficiency; the potential biological relevance of this finding is not known. Collectively, these results reveal a role for FN3K-dependent deglycation of NRF2 in cancer and imply that FN3K inhibitors may be worth exploring.

Sanghvi VR, Leibold J, Mina M, Mohan P, Berishaj M, Li Z, et al. The oncogenic action of NRF2 depends on de-glycation by fructosamine-3-kinase. Cell 2019;178:807–19.

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