Breast tumors are heterogeneous and composed of different sub-population of cells, each with dynamic roles that can change with stage, site and microenvironment. Cellular heterogeneity is in part due to cancer stem-like cells (CSC) that share properties with stem cells and associated with treatment-resistance. CSCs rewire metabolism to meet energy demands of increased growth and biosynthesis. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins. OGT/O-GlcNAc levels are elevated in multiple cancers and reducing OGT in cancer cells blocks tumor growth. Here, we report that breast CSCs enriched in mammosphere cultures contain elevated OGT... More
Breast tumors are heterogeneous and composed of different sub-population of cells, each with dynamic roles that can change with stage, site and microenvironment. Cellular heterogeneity is in part due to cancer stem-like cells (CSC) that share properties with stem cells and associated with treatment-resistance. CSCs rewire metabolism to meet energy demands of increased growth and biosynthesis. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins. OGT/O-GlcNAc levels are elevated in multiple cancers and reducing OGT in cancer cells blocks tumor growth. Here, we report that breast CSCs enriched in mammosphere cultures contain elevated OGT/O-GlcNAcylation. Inhibition of OGT genetically or pharmacologically reduced mammosphere forming efficiency, the CD44H/CD24L, NANOG+ and ALDH+ CSC population in breast cancer cells. Conversely, breast cancer cells over-expressing OGT increased mammosphere formation, CSC populations in-vitro and also increased tumor initiation and CSC frequency in-vivo. Furthermore, OGT regulates expression of a number of epithelial to mesenchymal transition (EMT) and cancer stem-like cell markers including CD44, NANOG, and c-Myc. In addition, we identify KLF8 as a novel regulator of breast cancer mammosphere formation and a critical target of OGT in regulating cancer stem-like cells. Implications: These findings demonstrate that OGT plays a key role in the regulation of breast CSCs in-vitro and tumor initiation in-vivo, in part, via regulation of KLF8 and thus inhibition of OGT may serve as a therapeutic strategy to regulate tumor-initiating activity.,Copyright ©2020, American Association for Cancer Research.
