Breast cancer; DNA methylation; Metastasis; Methylglyoxal; Tumor suppressor genes; Pyruvaldehyde; Humans; Pyruvaldehyde/metabolism; Cell Line, Tumor; Transcriptome; Gene Expression Regulation, Neoplastic; DNA Methylation; Triple Negative Breast Neoplasms/metabolism; Triple Negative Breast Neoplasms; Oncology; Cancer Research
Abstract :
[en] [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.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Dube, Gaurav; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Bizet, Martin; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Boumahd, Yasmine ; Université de Liège - ULiège > GIGA > GIGA Cancer
Gasmi, Imène ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Crake, Rebekah ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Bellier, Justine ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Nokin, Marie-Julie ; Université de Liège - ULiège > GIGA > GIGA Cancer - Tumours and development biology
Calonne, Emilie; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Deplus, Rachel; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Wissocq, Tom ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Peulen, Olivier ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Castronovo, Vincent; Metastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, Liège, Belgium
Fuks, François; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium ; WELBIO (Walloon Excellence in Lifesciences & Biotechnology), Brussels, Belgium
Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Fondation Rose et Jean Hoguet [BE] Fonds Léon Fredericq [BE] Fondation contre le Cancer [BE]
Funding text :
The authors are thankful to N. Maloujahmoum and F. Agirman (Metastasis Research Laboratory, University of Liège) for expert technical assistance. We thank Dr. K. Uchida (University of Tokyo, Japan) and Dr. D. Spiegel (Yale University, USA) for the kind gift of anti-argpyrimidine antibody and MBo probe, respectively. The authors acknowledge the scientific and technical support provided at the imaging/flow cytometry, genomic and viral vectors technology platforms of the GIGA-Research Institute (University of Liège, Belgium).A.B. is a Research Director at the National Fund for Scientific Research (FNRS), Belgium and F.F. is a ULB Professor. G.D. and T.W. are FNRS-Télévie PhD research fellows. G.D is also supported by Fondation Rose and Jean Hoguet. I.G. and R.C. are FNRS post-doctoral research fellows. A.B. lab is funded by grants from the FNRS, the University of Liège and Fondation Léon Fredericq. F.F. lab is funded by grants from the “Action de Recherche Concertée” (AUWB-2018–2023 ULB-No 7) and the Belgian Foundation Against Cancer (FCC 2016–086 FAF-F/2016/872). This work was supported by collaborative FNRS grants (PDR T.0188.18 and Télévie 7.4541.17) awarded to A.B and F.F.
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