Methylglyoxal: a novel upstream regulator of DNA methylation.
Breast cancer
DNA methylation
Metastasis
Methylglyoxal
Tumor suppressor genes
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
31 Mar 2023
31 Mar 2023
Historique:
received:
06
10
2022
accepted:
02
03
2023
medline:
3
4
2023
entrez:
30
3
2023
pubmed:
31
3
2023
Statut:
epublish
Résumé
Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate. Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts. GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival. This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC.
Sections du résumé
BACKGROUND
BACKGROUND
Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate.
METHODS
METHODS
Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts.
RESULTS
RESULTS
GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival.
CONCLUSION
CONCLUSIONS
This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC.
Identifiants
pubmed: 36998085
doi: 10.1186/s13046-023-02637-w
pii: 10.1186/s13046-023-02637-w
pmc: PMC10064647
doi:
Substances chimiques
Pyruvaldehyde
722KLD7415
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
78Subventions
Organisme : Fonds De La Recherche Scientifique - FNRS
ID : PDR T.0188.18
Organisme : Fonds De La Recherche Scientifique - FNRS
ID : PDR T.0188.18
Organisme : Fonds De La Recherche Scientifique - FNRS
ID : Télévie 7.4541.17
Organisme : Fonds De La Recherche Scientifique - FNRS
ID : Télévie 7.4541.17
Organisme : Action de recherche concertée
ID : AUWB-2018-2023
Organisme : Fondation contre le Cancer
ID : FCC 2016-086
Informations de copyright
© 2023. The Author(s).
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