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Access Type
WSU Access
Date of Award
January 2023
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Chemistry
First Advisor
Charlie Fehl
Abstract
Cancer cells usually exhibit increased glucose metabolism, but the downstream functional implications of abnormal glucose flux into cancer cells are difficult to mechanistically detect. Hyperglycemia linked metabolic diseases such as obesity and diabetes are increasingly associated with an increased cancer risk, more recently, with pre-menopausal triple-negative breast cancer (TNBC). However, identifying mechanisms for hyperglycemic disease-linked cancer risk remains a huge knowledge gap. The glucose-dependent protein modification with O-GlcNAc (O-linked N-acetylglucosamine) via the solitary human enzyme that catalyzes this activity, O-GlcNAc transferase (OGT), is one element of cellular sugar consumption that could potentially link bridge this gap. We employed chemical biology and molecular biology techniques to examine how this important protein post translational modification could be connected to the transcriptional regulatory enzyme tet-methylcytosine dioxygenase 1 (TET1) and its activities. We investigated the influence of hyperglycemia on cancer stem cells (CSC) pathway driven by TET1 in TNBC model and evaluated the connection to OGT activities. Our findings show that hyperglycemia stimulated O-GlcNAcylation of TET1 protein via OGT-catalyzed activity and this in turn upregulated TET1 epigenetic activities leading to the expansion of cancer stem cells in TNBC. Small molecule inhibition, RNA silencing, and overexpression of pathway components revealed a mechanism for glucose-driven CSC growth via TET1-O-GlcNAc. Furthermore, in hyperglycemic settings, activation of the pathway resulted in increased amounts of OGT synthesis via feed-forward regulation. We discovered that diet-induced obesity increased tumor OGT expression and O-GlcNAc levels in mice relative to lean littermates, implying that this pathway is relevant in an animal model of the hyperglycemic TNBC microenvironment. Our findings identified a mechanism by which hyperglycemia – linked diseases could trigger a CSC pathway in TNBC, and this route could be targeted to lower hyperglycemia-related breast cancer risk, especially for premenopausal TNBC. Also, our findings could pave the way for future research, premised on OGT inhibition to combat hyperglycemia as a risk factor for TNBC and other metabolic diseases-linked cancer types.
Recommended Citation
Ayodeji, Saheed Abolore, "The Roles Of O-Glcnac Protein Post Translational Modification In Hyperglycemia – Fueled Cancer And Development Of Chemical Tools To Map O-Glcnac Proteins Modification Sites In Disease Models." (2023). Wayne State University Dissertations. 3918.
https://digitalcommons.wayne.edu/oa_dissertations/3918