Methylglyoxal: a novel upstream regulator of DNA methylation

Abstract

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 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 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 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.

Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications

“…This means that, on the one hand, these structural changes underlie the production of the oncometabolite MGO. Cumulative research has focused on the emerging role of MGO as cellular oncometabolite involved in tumorigenesis-associated proliferative control, redox dysregulation, and epigenetic recoding [ 130 , 131 ]. Therefore, PTMs, HsTIM structural rearrangements, and MGO production represent a tri-partite component essential in maintaining the malignancy of cancer.…”

Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway

“…The study uncovered a pro-metastatic signature related to dicarbonyl stress in breast cancer cells. The MEK/ERK/SMAD1 pathway was hyperactivated under MGO stress conditions, connecting this pathway to a pro-metastatic phenotype [85]. High-throughput transcriptome profiling highlighted novel connections between MGO dicarbonyl stress, ECM remodeling, and enhanced cell migration [79].…”