| Title: |
GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance |
| Authors: |
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; Reginato, Mauricio |
| Source: |
Kimmel Cancer Center Faculty Papers |
| Publisher Information: |
Jefferson Digital Commons |
| Publication Year: |
2025 |
| Collection: |
Jefferson Digital Commons (Thomas Jefferson University, Philadelphia) |
| Subject Terms: |
humans; neoplastic stem cells; breast neoplasms; drug resistance; neoplasm; female; n-acetylglucosaminyltransferases; cell line; tumor; ubiquitin-protein ligases; ubiquitination; protein processing; post-translational; acetylglucosamine; Amino Acids; Peptides; and Proteins; Cells; Enzymes and Coenzymes; Oncology; Translational Medical Research |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://jdc.jefferson.edu/kimmelccfp/147; https://jdc.jefferson.edu/context/kimmelccfp/article/1147/viewcontent/GATAD2B_O_GlcNAcylation_Regulates_Breast_Cancer_Stem_like_Potential_and_Drug_Resistance.pdf; https://jdc.jefferson.edu/context/kimmelccfp/article/1147/filename/0/type/additional/viewcontent/Supplementary_Materials.zip |
| Availability: |
https://jdc.jefferson.edu/kimmelccfp/147; https://jdc.jefferson.edu/context/kimmelccfp/article/1147/viewcontent/GATAD2B_O_GlcNAcylation_Regulates_Breast_Cancer_Stem_like_Potential_and_Drug_Resistance.pdf; https://jdc.jefferson.edu/context/kimmelccfp/article/1147/filename/0/type/additional/viewcontent/Supplementary_Materials.zip |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.E7ADD8EC |
| Database: |
BASE |