Document Type
Article
Publication Date
3-8-2025
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.
Recommended Citation
Le Minh, Giang; Merzy, Jessica; Esquea, Emily; Ahmed, Nusaiba; Young, Riley; Sharp, Ryan; Dhameliya, Tejsi; Agana, Bernice; Lee, Mi-Hye; Bethard, Jennifer; Comte-Walters, Susana; Ball, Lauren; and Reginato, Mauricio, "GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance" (2025). Kimmel Cancer Center Faculty Papers. Paper 147.
https://jdc.jefferson.edu/kimmelccfp/147
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
40136647
Language
English
Included in
Amino Acids, Peptides, and Proteins Commons, Cells Commons, Enzymes and Coenzymes Commons, Oncology Commons, Translational Medical Research Commons
Comments
This article is the author's final published version in Cells, Volume 14, Issue 6, March 2025, Article number 398.
The published version is available at https://doi.org/10.3390/cells14060398.
Copyright © 2025 by the authors