Methylglyoxal: a novel upstream regulator of DNA methylation.

peer reviewed[en] 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

Une nouvelle connexion entre le stress dicarbonyl et la régulation épigéntique dans le cancer du sein

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

Nouveau lien entre le stress au dicarbonyle et la régulation épigénétique dans le cancer du sein triple négatif

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

Le méthylglyoxal réduit au silence épigénétiquement les gènes suppresseurs de tumeurs dans les 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

Une nouvelle connexion entre le stress dicarbonyle et la régulation épigénétique dans le cancer du sein

Methylglyoxal is a highly reactive compound derived from glycolysis. It can interact with several biological molecules like DNA, lipids or proteins leading to Advanced Glycation Product (AGE). Stress due to MG is known as a cause of several disease. It exists diverse defence mechanisms to regulate dicarbonyl stress and one of the most important is the Glyoxalase system composed of Glo1 and Glo2 enzymes. Epigenetic disorders are correlated with many human diseases including carcinogenesis. Aberrant DNA methylation or demethylation has been recognized as common molecular alterations in human neoplasia. To better understand the connexion between epigenetic disorders, metastatic properties and MG dicarbonyl stress in breast cancer, we used MDA-MB-231 cell line stably depleted for Glo1 to create an endogenous MG stress model. In this in vitro model, we observed the presence of a pro-metastatic signature under MG stress and a hypermethylation of the genome that was correlated with an increase of a de novo DNA methyltransferase (DNMT3A) protein expression. Interestingly, we could reverse DNMT3A over-expression via the use of MG scavengers like carnosine. As a perspective, we consider to investigate the MG stress-induce migratory capacities through the inhibition of DNMTs

Le stress carbonyle induit par le méthylglyoxal dans la progression du mélanome et la réponse aux thérapies

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This dicarbonyl compound is highly reactive and induces the formation of advanced glycation end-products implicated in several pathologies, including cancer. All mammalian cells have an enzymatic defense against MG, composed by glyoxalases GLO1 and GLO2, that converts MG to D-lactate. Aldo-keto reductase enzymes can also detoxify MG to acetol and lactaldehyde. Melanoma, the most deadly form of skin cancer, is associated with BRAF or NRAS mutations. These mutations are characterized by a glycolytic switch thus leading to potential accumulation of MG stress

Le stress carbonyle induit par le méthylglyoxal dans la progression du mélanome et la réponse aux thérapies

Cancer cells generally rely on aerobic glycolysis as a major source of energy and building blocks. Increased glycolysis in cancer cells leads to spontaneous production of Methylglyoxal (MG). This dicarbonyl compound is highly reactive and induces the formation of advanced glycation end-products implicated in several pathologies, including cancer. All mammalian cells have an enzymatic defense against MG, composed by glyoxalases GLO1 and GLO2, that converts MG to D-lactate. Aldo-keto reductase enzymes can also detoxify MG to acetol and lactaldehyde. Melanoma, the most deadly form of skin cancer, is associated with BRAF or NRAS mutations. These mutations are characterized by a glycolytic switch thus leading to potential accumulation of MG stress

Le stress du dicarbonyle induit une dérégulation épigénétique conduisant à un phénotype pro-migratoire dans le cancer du sein.

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