The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.
Animals
Carcinoma, Hepatocellular
/ metabolism
Female
Gene Knockdown Techniques
Glucose
/ metabolism
Glycosylation
HEK293 Cells
Hep G2 Cells
Heterografts
Humans
Kelch-Like ECH-Associated Protein 1
/ metabolism
Liver Neoplasms
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Nude
Mice, SCID
NF-E2-Related Factor 2
/ metabolism
Phosphotransferases (Alcohol Group Acceptor)
/ genetics
Proto-Oncogene Proteins c-myc
/ metabolism
Transduction, Genetic
EGFR
FN3K
KEAP1
NRF2
de-glycation
fructosamine
glucose
glycation
hepatocellular carcinoma
redox
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
08 08 2019
08 08 2019
Historique:
received:
05
02
2019
revised:
23
06
2019
accepted:
17
07
2019
entrez:
10
8
2019
pubmed:
10
8
2019
medline:
10
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31398338
pii: S0092-8674(19)30830-X
doi: 10.1016/j.cell.2019.07.031
pmc: PMC6693658
mid: NIHMS1535542
pii:
doi:
Substances chimiques
KEAP1 protein, human
0
Keap1 protein, mouse
0
Kelch-Like ECH-Associated Protein 1
0
MYC protein, human
0
Myc protein, mouse
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Nfe2l2 protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
fructosamine-3-kinase
EC 2.7.1.-
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
807-819.e21Subventions
Organisme : NIH HHS
ID : U54 OD020355
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190384
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NIH HHS
ID : S10 OD010598
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207217
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183876
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA192937
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217694
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142798
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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