Article ; Online: Methylglyoxal: a novel upstream regulator of DNA methylation.
Journal of experimental & clinical cancer research : CR
2023 Volume 42, Issue 1, Page(s) 78
Abstract: 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, ... ...
| Abstract | 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. |
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| MeSH term(s) | Humans ; DNA Methylation ; Triple Negative Breast Neoplasms/metabolism ; Pyruvaldehyde/metabolism ; Cell Line, Tumor ; Transcriptome ; Gene Expression Regulation, Neoplastic |
| Chemical Substances | Pyruvaldehyde (722KLD7415) |
| Language | English |
| Publishing date | 2023-03-31 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 803138-1 |
| ISSN | 1756-9966 ; 0392-9078 |
| ISSN (online) | 1756-9966 |
| ISSN | 0392-9078 |
| DOI | 10.1186/s13046-023-02637-w |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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