Methylglyoxal epigenetically silences tumor suppressor genes in TNBC

Triple-negative breast cancer (TNBC) represents the breast cancer subtype with the worse prognosis and TNBC metabolic profiling indicates that this subtype of breast tumors is generally glycolytic. Methylglyoxal (MG), a very reactive dicarbonyl molecule is derived from glycolysis. In the context of this project we wanted to better understand the relation between MG stress and epigenetic in TNBCs. For that we generated a breast cancer cell line stably depleted for GLO1 (the major defense against MG) to induce an endogenous MG stress.
RNA sequencing analysis revealed a pro-metastatic MG signature comprising the regulation of metastatic-related genes expression. Among them, the de novo DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) were found significantly increased, suggesting the potential impact of MG stress on epigenetic regulation. Subsequently, we performed a genome wide methylation analysis with 850K CpGs array on GLO1-depleted cells to point to a significant global hypermethylation. The integrative analysis of gene expression data with gene regulatory region methylation status revealed a significant down-regulation of tumor suppressor genes under MG stress in cancer cells and in several cohorts of breast cancer patients. This transcriptomic MG-signature allowed the clustering of high MG stress patients having the worst prognosis, correlating MG stress with grade.