有氧酵解，也称沃伯格效应，在多种实体瘤中，包括乳腺癌中主要上调。我们先前曾报道，甲基乙二醛（MG）是酵解的一种非常反应性副产品，在三阴性乳腺癌（TNBC）细胞中出人意料地增强了转移潜能。MG和MG衍生的糖基化产物已与各种疾病，如糖尿病、神经退行性疾病和癌症发生相关。甘氧化酶1（GLO1）通过将MG解毒转化为D-乳酸发挥抗糖基化防御作用。在此，我们使用了验证过的稳定GLO1耗尽模型，在TNBC细胞中导致MG应激。使用基因组规模的DNA甲基化分析，我们报告这种状态导致TNBC细胞和异种移植体中的DNA高甲基化。GLO1耗竭的乳腺癌细胞显示DNMT3B甲基转移酶表达升高，以及转移相关肿瘤抑制基因的显著丢失，这些结果是通过甲基组和转录组数据的综合分析得出的。有趣的是，MG清除剂被揭示为与典型的DNA去甲基化剂一样有效，可以触发被沉默基因的再表达。重要的是，我们绘制了一个表达出良好的MG表观遗传标记，在生存方面有效地划分了TNBC患者。本研究强调了MG作为新的表观遗传调节因子，出现在沃伯格效应下游，对乳腺癌代谢产物的重要性，并提出MG清除剂可以逆转TNBC中基因表达的改变模式。©2023年作者。

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.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.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.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.© 2023. The Author(s).