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

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated cancer cells to iron-dependent cell death, ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between ferroptosis inducers, erastin and RSL3, and WJ460

Role of myoferlin in mitochondrial dynamics and metabolic fitness of pancreas cancer

Pancreatic cancer is the 7th most common cause of cancer mortality in the world. It is predicted to become the second leading cause of cancer-related death in 2030. Myoferlin is a 230 kDa protein overexpressed in pancreatic cancer. Recently, our team showed a fragmentation of the mitochondrial network in PDAC cells when myoferlin was depleted using siRNA. Understanding the mechanism underlying this mitochondrial disruption would be of great interest as mitochondria are major actors in cancer development, progression and resistanceRole of myoferlin in mitochondrial dynamics and metabolic fitness of pancreatic cance

Role of myoferlin in mitochondrial dynamics and metabolic fitness of PDAC

Our data strongly suggest that myoferlin interacts with MFN. Indeed, if myoferlin is a part of the mitochondrial fusion machinery, its silencing together with an unopposed fission would lead to mitochondrial fragmentation.Role of myoferlin in mitochondrial dynamics and metabolic fitness of pancreatic cance

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