New connection between tumor energy metabolism and epigenetic regulation
The team of Dr. Akeila Bellahcène, FNRS Research Director, at the Metastasis Research Laboratory (GIGA-Cancer) has established a new connection between tumor energy metabolism and epigenetic regulation. This new study, conducted in collaboration with Prof. François Fuks (ULB), reveals an unsuspected link between methylglyoxal, a highly reactive by-product of glycolysis, and the expression of the main enzymes that catalyze DNA methylation: the DNA methyltransferases. This work, published in the Journal of Experimental Clinical Cancer Research, reveals that mammary cancer cells, under methylglyoxal stress, see a significant increase in methylation at the genome level, thus favoring the extinction of many tumor suppressor genes. This original study highlights the importance of methylglyoxal as an oncometabolite present downstream of the Warburg effect and as a novel epigenetic regulator and proposes methylglyoxal scavengers to counteract the loss of tumor suppressor gene expression generally associated with the initiation and progression of triple negative breast cancer.
Aerobic glycolysis, also known as the Warburg effect, is upregulated in a variety of solid tumors, including breast cancer. In glycolytic tumors, the accumulation of methylglyoxal induces the glycation of proteins and nucleic acids with repercussions on their functions within the cell. Dr. Bellahcène's team has previously demonstrated that glycation stress increases the metastatic potential of triple negative breast cancer cells. In this study, the researchers used a strategy consisting of the stable depletion of glyoxalase 1, the enzyme that detoxifies methylglyoxal, to induce glycation stress in triple-negative breast cancer cells. Using genome-wide DNA methylation analysis, they found that this condition resulted in DNA hypermethylation in these cells. Consistently, this methylglyoxal stress model identified elevated expression of the methyltransferase DNMT3B associated with a significant loss of expression of metastasis-related tumor suppressor genes that was validated through an integrated analysis of the methylome and transcriptome data. Interestingly, methylglyoxal scavengers (carnosine and aminoguanidine) were found to be as potent as conventional DNA demethylating agents (5-AZA) in inducing the re-expression of all tumor suppressor genes analyzed in this model.
Importantly, this original study has allowed the characterization of an epigenomic signature of methylglyoxal that effectively stratifies triple negative breast cancer tumors with bad prognosis and thus allows the identification of a subgroup of patients likely to respond favorably to methylglyoxal neutralizing agents. Further pre-clinical studies are expected to validate the potential interest of such substances for the treatment of triple negative breast cancer.
Finally, methylglyoxal and its advanced glycation products have been associated with diseases other than cancer, such as diabetes and Parkinson's and Alzheimer's neurodegenerative disorders. This discovery therefore opens the way to potential new treatments for these so-called diseases of civilization.
This study was made possible thanks to the support of the FNRS (FNRS PDR grant T.0188.18), Télévie (grant 7.4541.17), the University of Liège and the Léon Fredericq Foundation.
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Reference
Methylglyoxal: a novel upstream regulator of DNA methylation.
Dube G, Tiamiou A, Bizet M, Boumahd Y, Gasmi I, Crake R, Bellier J, Nokin MJ, Calonne E, Deplus R, Wissocq T, Peulen O, Castronovo V, Fuks F, Bellahcène A.
J Exp Clin Cancer Res. 2023 Mar 31;42(1):78.
doi: 10.1186/s13046-023-02637-w. PMID: 36998085
