Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Cancer cell international - 23(2023), 1 vom: 25. Mai, Seite 102 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ayodeji, Saheed A [VerfasserIn] |
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| Links: |
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| Themen: |
Chemical biology |
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| Anmerkungen: |
Date Revised 02.03.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1186/s12935-023-02942-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357337123 |
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| 100 | 1 | |a Ayodeji, Saheed A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 02.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Chemical biology | |
| 650 | 4 | |a Epigenetics | |
| 650 | 4 | |a Glycobiology | |
| 650 | 4 | |a Hyperglycemia | |
| 650 | 4 | |a Metabolic disease | |
| 650 | 4 | |a O-GlcNAc transferase | |
| 650 | 4 | |a Obesity | |
| 650 | 4 | |a TET1 | |
| 650 | 4 | |a TNBC | |
| 650 | 4 | |a Tumorigenesis | |
| 700 | 1 | |a Bao, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Teslow, Emily A |e verfasserin |4 aut | |
| 700 | 1 | |a Polin, Lisa A |e verfasserin |4 aut | |
| 700 | 1 | |a Dyson, Greg |e verfasserin |4 aut | |
| 700 | 1 | |a Bollig-Fischer, Aliccia |e verfasserin |4 aut | |
| 700 | 1 | |a Fehl, Charlie |e verfasserin |4 aut | |
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