PMID: 32858971 RLIMS-P 1 Check other iTextMine results Issue Report
Title
| 1. | DJ-1 Proteoforms in Breast Cancer Cells: The Escape of Metabolic Epigenetic Misregulation. |
Abstract
| 2. | Enhanced glycolysis is a hallmark of breast cancer. |
| 3. | In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. |
| 4. | Together with glucose, methylglyoxal (MGO), a byproduct of glycolysis, is considered the main glycating agent. |
| 5. | MGO is highly diffusible, enters the nucleus, and can react with easily accessible lysine- and arginine-rich tails of histones. |
| 6. | Glycation adducts on histones undergo oxidization and further rearrange to form stable species known as advanced glycation end-products (AGEs). |
| 7. | This modification alters nucleosomes stability and chromatin architecture deconstructing the histone code. |
| 8. | Formation of AGEs has been associated with cancer, diabetes, and several age-related diseases. |
| 9. | Recently, DJ-1, a cancer-associated protein that protects cells from oxidative stress, has been described as a deglycase enzyme. |
| 10. | Although its role in cell survival results still controversial, in several human tumors, its expression, localization, oxidation, and phosphorylation were found altered. |
| 11. | This work aimed to explore the molecular mechanism that triggers the peculiar cellular compartmentalization and the specific post-translational modifications (PTM) that, occurring in breast cancer cells, influences the DJ-1 dual role. |
| 12. | Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |
| 13. | Notably, this threonine is in addition to histidine 126, a key residue involved in the formation of catalytic triade (glu18-Cys106-His126) inside the glioxalase active site of DJ. |
| 14. | Interestingly, we found that pharmacological modulation of Akt pathway induces a functional tuning of DJ-1 proteoforms, as well as their shuttle from cytosol to nucleus, pointing out that pathway as critical in the development of DJ-1 pro-tumorigenic abilities. |
| 15. | Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. |
| 16. | In normal conditions, DJ-1 acts as a redox-sensitive chaperone and as an oxidative stress sensor. |
| 17. | In cancer cells, glycolytic rewiring, inducing increased reactive oxygen species (ROS) levels, enhances AGEs products. |
| 18. | Alongside, the moderate increase of ROS enhances Akt signaling that induces DJ-1-phosphorylation. |
| 19. | When phosphorylated DJ-1 increases its glyoxalase activity, the level of AGEs on histones decreases. |
| 20. | Therefore, phospho-DJ-1 prevents glycation-induced histones misregulation and its Akt-related hyperactivity represents a way to preserve the epigenome landscape sustaining proliferation of cancer cells. |
| 21. | Together, these results shed light on an interesting mechanism that cancer cells might execute to escape the metabolic induced epigenetic misregulation that otherwise could impair their malignant proliferative potential. |
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Legend: SUBSTRATE KINASE INTERACTANT SITE GENE MIRNA ANOMALY EXPRESSION DISEASE OUTCOME/RESPONSE SR_DRUG DRUG CELL TRIGGER Normalized
Tool: RLIMS-P
| PTM enzyme | Substrate | Site | Sentence |
|---|---|---|---|
| DJ-1 (Q99497) | 15, 18, 19, 20 |