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Dissertation
Understanding role of OGT/O-GlcNAcylation in regulating breast cancer stem cell function
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2023
DOI:
https://doi.org/10.17918/00001892
Abstract
Breast cancer is a major health challenge for women. Patient outcomes are worsened by the heterogenous nature these tumors. Intratumor heterogeneity is driven by a subset of cancer cells termed cancer stem cells (CSCs). CSCs are capable of self-renewing and driving tumor growth, and drug-resistance. The protein modification O-GlcNAcylation and its enzyme OGT function to connect nutrient status to cellular signaling. OGT/O-GlcNAc are highly expressed in breast cancer and required to promote CSCs function in breast cancer. However, the mechanism of OGT/O-GlcNAc in regulating CSCs remains unclear. Here, we identified two novel mechanisms by which OGT/O-GlcNAc can regulate CSCs properties in breast cancer. We show that OGT can form a mutual-positive-feedback loop with KLF8 to regulate CSCs function in breast cancer via regulating expression of CSCs co-factors. Importantly, KLF8 also promotes paclitaxel-resistance of breast cancer cells. Secondly, we discovered that OGT/O-GlcNAc regulates GATAD2B, a key component of the NuRD complex. GATAD2B is highly expressed in breast cancer and is associated with poor survival. GATAD2B is critical to maintain and promote CSCs-phenotypes in breast cancer cells via regulating expression of CSCs-co-factors. GATAD2B also promotes paclitaxel-resistance of breast cancer cells. We also showed that GATAD2B is O-GlcNAcylated, which protects GATAD2B from proteasomal degradation mediated by the E3-ligase ITCH. ITCH inhibition increased GATAD2B level and CSCs function. Importantly, GATAD2B O-GlcNAcylation is critical for CSCs-phenotype and paclitaxel-resistance. Together, we identified KLF8 and GATAD2B as targets of OGT/O-GlcNAc in regulating CSCs-phenotypes and chemoresistance, which may serve as biomarkers, and targets for improving breast cancer treatments.
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Details
- Title
- Understanding role of OGT/O-GlcNAcylation in regulating breast cancer stem cell function
- Creators
- Giang Le Minh
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 205 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991021807413604721