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Thesis
Regulation of NuRD complex proteins by O-GlcNAc transferase in breast cancer cells
Master of Science (M.S.), Drexel University
Apr 2022
DOI:
https://doi.org/10.17918/00001227
Abstract
Women in their lifetime have a one in eight chance of being diagnosed with breast cancer and, in the U.S., breast cancer is the second leading cause of female deaths. Triple negative breast cancer (TNBC) is the most lethal type of breast cancer, and currently has no targeted treatment. O- GlcNAcylation, a post translational modification of nuclear and cytoplasmic proteins by O-GlcNAc transferase (OGT), is upregulated in breast cancer. OGT/ O-GlcNAcylation regulates stem cells and contributes to cancer hallmarks including cell survival and proliferation. Recently, our lab has shown that OGT regulates breast cancer stem-like phenotypes which is associated with cancer progression and resistance to chemotherapy. Using a proteomic approach, we identified 143 proteins elevated in TNBC cells following increased O-GlcNAcylation. Six of these proteins function in the Nucleosome Remodeling and Deacetylase (NuRD) Complex, which has been shown to be involved in embryonic stem cell (SC) self-renewal and implicated in tumorigenesis. Here, we validate that NuRD complex proteins GATAD2B, GATAD2A, MTA2, RBBP4 and HDAC2 are regulated by OGT. We show that pharmacologically increasing O-GlcNAc levels or overexpressing OGT in TNBC cells elevated NuRD protein levels. Conversely, targeting OGT genetically in breast cancer cells reduces expression of NuRD complex proteins. Importantly, we show that GATAD2B levels are enriched in mammosphere formation assays and that knockdown of GATAD2B in TNBC cells blocks mammosphere formation, suggesting a possible novel role for GATAD2B regulating breast cancer SC phenotypes. Lastly, we show that overexpression of GATAD2B in TNBC cells promotes selective resistance to chemotherapeutic agent paclitaxel, but not to doxorubicin in vitro. Thus, O-GlcNAc regulation of the NuRD complex and specifically GATAD2B may be a novel mechanism that regulates breast cancer stem cell phenotypes and chemoresistance in TNBC cells.
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Details
- Title
- Regulation of NuRD complex proteins by O-GlcNAc transferase in breast cancer cells
- Creators
- Ryan Sharp
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vi, 44 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991018530915504721