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Journal article
GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance
Cells, v 14(6), 398
08 Mar 2025
PMID: 40136647
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Abstract
The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression of self-renewal factors and CSCs population. O-GlcNAcylation of GATAD2B at the C-terminus protects GATAD2B from ubiquitination and proteasomal degradation in breast cancer cells. We identify ITCH as a novel E3 ligase for GATAD2B and show that targeting ITCH genetically increases GATAD2B levels and increases CSCs phenotypes. Lastly, we show that overexpression of wild-type GATAD2B, but not the mutant lacking C-terminal O-GlcNAc sites, promotes mammosphere formation, expression of CSCs factors and drug resistance. Together, we identify a key role of GATAD2B and ITCH in regulating CSCs in breast cancer and GATAD2B O-GlcNAcylation as a mechanism regulating breast cancer stem-like populations and promoting chemoresistance.
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Details
- Title
- GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance
- Creators
- Giang Le Minh - Drexel UniversityJessica Merzy - Drexel University, Biochemistry and Molecular BiologyEmily Esquea - Drexel University, Biochemistry and Molecular BiologyNusaiba N Ahmed - Drexel University, College of MedicineRiley G Young - Drexel University, Biochemistry and Molecular BiologyRyan J. Sharp - Drexel UniversityTejsi Dhameliya - Drexel UniversityBernice Agana - Medical University of South CarolinaMi-Hye Lee - Medical University of South CarolinaJennifer R. Bethard - Medical University of South CarolinaSusana Comte-Walters - Medical University of South CarolinaMauricio J Reginato (Corresponding Author) - Drexel University, Biochemistry and Molecular Biology
- Publication Details
- Cells, v 14(6), 398
- Publisher
- MDPI
- Number of pages
- 25
- Grant note
- National Institutes of Health: 1P30CA138313-24A5 National Institutes of Health: 1T32CA193201-24A2 National Institutes of Health: 1P20GM103542-24A3 National Institutes of Health: 1UL1TR001450-24A3
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001452039700001
- Scopus ID
- 2-s2.0-105001315156
- Other Identifier
- 991022032972704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology