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Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer

التفاصيل البيبلوغرافية
العنوان: Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer
المؤلفون: Saheed A. Ayodeji, Bin Bao, Emily A. Teslow, Lisa A. Polin, Greg Dyson, Aliccia Bollig-Fischer, Charlie Fehl
المصدر: Cancer Cell International, Vol 23, Iss 1, Pp 1-18 (2023)
بيانات النشر: BMC, 2023.
سنة النشر: 2023
المجموعة: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
LCC:Cytology
مصطلحات موضوعية: O-GlcNAc transferase, Hyperglycemia, TNBC, Tumorigenesis, Metabolic disease, Glycobiology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671
الوصف: Abstract Background Enhanced glucose metabolism is a feature of most tumors, but downstream functional effects of aberrant glucose flux are difficult to mechanistically determine. Metabolic diseases including obesity and diabetes have a hyperglycemia component and are correlated with elevated pre-menopausal cancer risk for triple-negative breast cancer (TNBC). However, determining pathways for hyperglycemic disease-coupled cancer risk remains a major unmet need. One aspect of cellular sugar utilization is the addition of the glucose-derived protein modification O-GlcNAc (O-linked N-acetylglucosamine) via the single human enzyme that catalyzes this process, O-GlcNAc transferase (OGT). The data in this report implicate roles of OGT and O-GlcNAc within a pathway leading to cancer stem-like cell (CSC) expansion. CSCs are the minor fraction of tumor cells recognized as a source of tumors as well as fueling metastatic recurrence. The objective of this study was to identify a novel pathway for glucose-driven expansion of CSC as a potential molecular link between hyperglycemic conditions and CSC tumor risk factors. Methods We used chemical biology tools to track how a metabolite of glucose, GlcNAc, became linked to the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1) as an O-GlcNAc post-translational modification in three TNBC cell lines. Using biochemical approaches, genetic models, diet-induced obese animals, and chemical biology labeling, we evaluated the impact of hyperglycemia on CSC pathways driven by OGT in TNBC model systems. Results We showed that OGT levels were higher in TNBC cell lines compared to non-tumor breast cells, matching patient data. Our data identified that hyperglycemia drove O-GlcNAcylation of the protein TET1 via OGT-catalyzed activity. Suppression of pathway proteins by inhibition, RNA silencing, and overexpression confirmed a mechanism for glucose-driven CSC expansion via TET1-O-GlcNAc. Furthermore, activation of the pathway led to higher levels of OGT production via feed-forward regulation in hyperglycemic conditions. We showed that diet-induced obesity led to elevated tumor OGT expression and O-GlcNAc levels in mice compared to lean littermates, suggesting relevance of this pathway in an animal model of the hyperglycemic TNBC microenvironment. Conclusions Taken together, our data revealed a mechanism whereby hyperglycemic conditions activated a CSC pathway in TNBC models. This pathway can be potentially targeted to reduce hyperglycemia-driven breast cancer risk, for instance in metabolic diseases. Because pre-menopausal TNBC risk and mortality are correlated with metabolic diseases, our results could lead to new directions including OGT inhibition for mitigating hyperglycemia as a risk factor for TNBC tumorigenesis and progression.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1475-2867
Relation: https://doaj.org/toc/1475-2867
DOI: 10.1186/s12935-023-02942-6
URL الوصول: https://doaj.org/article/544cf2f65d474bdbaf1e18dafcbe805d
رقم الأكسشن: edsdoj.544cf2f65d474bdbaf1e18dafcbe805d
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:14752867
DOI:10.1186/s12935-023-02942-6