Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium.
Metastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, Liège, Belgium.
J Exp Clin Cancer Res. 2023 Mar 31;42(1):78. doi: 10.1186/s13046-023-02637-w.
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.
有氧糖酵解，又称瓦博格效应，在多种实体瘤中显著上调，包括乳腺癌。我们之前报道过，甲基乙二醛（MG），一种糖酵解的非常活跃的副产物，出人意料地增强了三阴性乳腺癌（TNBC）细胞的转移潜能。MG 和 MG 衍生的糖化产物与各种疾病有关，如糖尿病、神经退行性疾病和癌症。糖氧还蛋白 1（GLO1）通过将 MG 解毒为 D-乳酸来发挥抗糖化防御作用。
在这里，我们使用我们验证的模型，由稳定的 GLO1 耗竭诱导 TNBC 细胞中的 MG 应激。使用全基因组规模的 DNA 甲基化分析，我们报告说，这种情况导致 TNBC 细胞和异种移植物中的 DNA 超甲基化。
GLO1 耗尽的乳腺癌细胞表现出 DNMT3B 甲基转移酶的高表达，以及转移相关肿瘤抑制基因的显著丢失，这是通过甲基组和转录组数据的综合分析评估的。有趣的是，MG 清除剂被证明与典型的 DNA 去甲基化剂一样有效地触发代表性沉默基因的重新表达。重要的是，我们描绘了一个表观基因组 MG 特征，根据生存有效地对 TNBC 患者进行分层。
这项研究强调了沃伯格效应下游的 MG 致癌代谢物作为一种新型表观遗传调节剂的重要性，并提出了 MG 清除剂来逆转 TNBC 中改变的基因表达模式。
