No abstract

The quiescent/slow‐cycling state preserves the self‐renewal capacity of cancer stem cells (CSCs) and leads to the therapy resistance of CSCs. The mechanisms maintaining CSCs quiescence remain largely unknown. Here, it is demonstrated that lower expression of MAN1A1 in glioma stem cell (GSC) resulted in the formation of high‐mannose type N‐glycan on CD133. Furthermore, the high‐mannose type N‐glycan of CD133 is necessary for its interaction with DNMT1. Activation of p21 and p27 by the CD133–DNMT1 interaction maintains the slow‐cycling state of GSC, and promotes chemotherapy resistance and tumorigenesis of GSCs. Elimination of the CD133–DNMT1 interaction by a cell‐penetrating peptide or MAN1A1 overexpression inhibits the tumorigenesis of GSCs and increases the sensitivity of GSCs to temozolomide. Analysis of glioma samples reveals that the levels of high‐mannose type N‐glycan are correlated with glioma recurrence. Collectively, the high mannose CD133–DNMT1 interaction maintains the slow‐cycling state and tumorigenic potential of GSC, providing a potential strategy to eliminate quiescent GSCs.

No abstract

CD133 is a widely used cell surface marker of cancer stem cells that plays an important role in tumor initiation and metastasis. Increasing evidence shows that CD133 is secreted to the extracellular space. However, the underlying mechanisms of CD133 secretion remain largely unknown. In this study, we report that secreted CD133 has a complex‐type N‐glycosylation and is modified by beta1,6GlcNAc N‐glycan. We found that inhibition of CD133 complex‐type N‐glycosylation by swainsonine does not affect the membrane localization of CD133, but significantly reduces CD133 secretion and promotes its accumulation in early endosomes. Moreover, swainsonine reduces CD133 secretion by reducing its mono‐ubiquitination and inhibiting the interaction between CD133 and Tsg101. These findings reveal a new mechanism of glycosylation‐dependent secretion of CD133.

The monocyte adhesion to endothelial cells is an early step in chronic inflammation. Interferon-γ (IFN-γ) is regarded as a master regulator of inflammation development. However, the significance of IFN-γ in the monocyte adhesion to endothelial cells remains largely unknown. In this study, we found that IFN-γ increased PD-L1 transcription in endothelial cells through IRF-1 transcription factor, and subsequently enhanced the adhesion of monocyte to endothelial cells. PD-L1 in endothelial cells interacted with CD169/Siglec 1 in monocyte depending on the α2,3-sialylation of PD-L1. ST3Gal4 (ST3β-galactoside α-2,3-sialyltransferase 4) was the major glycosyltransferase responsible for the α2,3-sialylation of PD-L1. Down-regulation of α2,3-sialylation of PD-L1 by ST3Gal4 knockdown reduced the PD-L1-CD169 interaction. Purified PD-L1 protein with α2,3-sialylation, but not PD-L1 protein without α2,3-sialylation, reduced IFN-γ-induced monocytes adhesion to endothelial cells. Collectively, the interaction between PD-L1 and CD169 promoted monocytes adhesion to endothelial cells. Our findings provide a new mechanism of monocytes adhesion to endothelial cells.