| Popis: |
Tumors are heterogeneous and composed of different sub-populations of cells, each with dynamic roles that can change with stage, site and microenvironment. Tumor initiating cells (TIC) are one such subpopulation that shares properties with cancer stem-like cells and when isolated and transplanted into an animal and can regenerate the whole heterogenous tumor. Chemotherapy targets rapidly dividing cells and may not readily target these TICs thereby contributing to resistance and relapse. TICs, like cancer cells, rewire metabolism to meet energy demands of increased growth and biosynthesis. The hexosamine biosynthetic pathway utilizes glucose to generate UDP-GlcNAc. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins, many of which participate in signaling cascades. OGT/O-GlcNAc levels are elevated in multiple cancers and reducing OGT in breast cancer cells blocks growth in-vitro and in-vivo. Here, we show that breast cancer cells enriched for self-renewing TICs in mammosphere cultures, contain elevated OGT/O-GlcNAcylation. Inhibition of OGT genetically or pharmacologically reduces mammosphere forming efficiency and the CD44H/CD24L, NANOG+ and ALDH+ TIC population in breast cancer cells. Conversely, mammospheres formation increases in breast cancer cells over-expressing OGT, TIC populations in-vitro and also increases tumor initiation and stem cell frequency in-vivo. OGT also promotes epithelial to mesenchymal transition (EMT), a phenomenon on which cells rely heavily to maintain stemness. Furthermore, OGT regulates expression of a number of cancer stem-like markers including CD44, NANOG, and c-Myc. In addition, we identify KLF8 as a novel regulator of breast cancer mammosphere formation and critical target of OGT in regulating tumor initiating potential. These results suggest that OGT plays a key role in regulation of breast cancer tumor initiating cells in-vitro and in-vivo. |
