O-GlcNAcylation Enhances Double-Strand Break Repair, Promotes Cancer Cell Proliferation, and Prevents Therapy-Induced Senescence in Irradiated Tumors
| Autor: | Sara Warrington, Elena V. Efimova, Stephen J. Kron, Aishwarya Ramamurthy, Yue Liu, Steve S. Lee, Amy Catherine Flor, Natalia Ricco, Oliver K. Appelbe, Tamica Collins, Donald Wolfgeher, Vytautas P. Bindokas |
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| Rok vydání: | 2019 |
| Předmět: |
Proteomics
0301 basic medicine Genome instability Senescence Cancer Research DNA Repair DNA damage DNA repair Acylation Glutamine Mice Nude Breast Neoplasms N-Acetylglucosaminyltransferases Article Genomic Instability Cell Line Epigenesis Genetic Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Animals Humans DNA Breaks Double-Stranded Epigenetics Molecular Biology Cellular Senescence Cell Proliferation Chemistry Cancer Hexosamines medicine.disease Biosynthetic Pathways Chromatin Glucose HEK293 Cells 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Female Protein Processing Post-Translational |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein posttranslational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double-strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response (DDR) in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DDR pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase or simply treating animals with GlcNAc protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DDR, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: The finding that the HBP, via its impact on protein O-GlcNAcylation, is a key determinant of the DDR in cancer provides a mechanistic link between metabolic reprogramming, genomic instability, and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization. |
| Databáze: | OpenAIRE |
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