Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in TNBC

Ayodeji, S.; Bao, B.; Teslow, E. A.; Polin, L. A.; Dyson, G.; Bollig-Fischer, A.; Fehl, C.

doi:10.1101/2022.03.14.484003

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bioRxiv · 10.1101/2022.03.14.484003

Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in TNBC

Ayodeji, S.·Bao, B.·Teslow, E. A.·Polin, L. A.·Dyson, G.·Bollig-Fischer, A.·Fehl, C.

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Abstract

Enhanced glucose metabolism is a feature of almost all cancers, but downstream functional effects of aberrant glucose flux are difficult to mechanistically determine. The objective of this study is to characterize a mechanism by which elevated glucose level drives a tumorigenic pathway in triple negative breast cancer (TNBC). We used chemical biology methods to track how a metabolite of glucose, N-acetylglucosamine (GlcNAc), is linked to the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1) as an O-linked GlcNAc post translational modification (O-GlcNAc). In this work, we revealed that intracellular protein glycosylation by O-GlcNAc is driven by high glucose levels in TNBC models, including on TET1. A single enzyme, O-GlcNAc transferase (OGT), is responsible for catalyzing protein modification of O-GlcNAc. We showed that OGT activity is higher in TNBC cell lines compared to non-tumor breast cell lines and is associated with hyperglycemia. Furthermore, enhanced OGT activity activated a pathway for cancer stem-like cell (CSC) reprogramming in TNBC cells. In our model, O-GlcNAcylated TET1 upregulated expression of splicing factor TAR-DNA binding protein (TARDBP), which drives CSC induction as well as higher OGT levels. We show that this OGT-TET1-TARDBP axis "feeds-forward" in hyperglycemic conditions both in cell lines and diet-induced obese mice, which displayed higher blood glucose levels and tumor O-GlcNAc levels than lean littermates. This data converges on a novel pathway whereby hyperglycemia drives aberrant OGT activity, activating a pathway for CSC induction in TNBC. Our findings partially explain a key aspect of how obesity is associated with TNBC risk and negative outcomes. Statement of ImplicationThis work presents a novel mechanism to explain how obesity is a risk factor for triple-negative breast cancer via elevated sugar-transfer activity by O-GlcNAc transferase in hyperglycemia, leading to the induction of a cancer stem-like cells and revealing a targetable pathway in obesity-associated tumors.

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Ayodeji, S., Bao, B., Teslow, E. A., Polin, L. A., Dyson, G., Bollig-Fischer, A., Fehl, C.. 2022-03-16. Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in TNBC. https://doi.org/10.1101/2022.03.14.484003

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