Abstract
Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin β1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin β1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin β1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma.
Highlights
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) that is distributed on the cell surface and in the extracellular space
The results revealed that non-tumor regions of the normal brain were consistently negative for the expression of CS56 (n = 3), while diverse staining patterns were observed in CS56-positive tumor tissue, including intense staining of capillaries, intense staining of adjacent areas surrounding blood vessels, and a weak, moderate, or intense staining that was spread across the tumor tissues (Figure 1A)
We have previously demonstrated that chondroitin sulfate synthase 1 (CHSY1) functions as the dominant CS synthase in human glioma cells, and its expression is significantly correlated with the anti-CS antibody (CS56) staining intensity in glioma tissues [17]
Summary
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) that is distributed on the cell surface and in the extracellular space. Previous studies have shown that CS is the most abundant GAG in the ECM of the central nervous system (CNS) [3,4]. The CSPGs in the CNS participate in neural development and support the microenvironment for neural growth and repair [3,4,5]. They are known to modulate neural stemness phenotypes, cell proliferation, and differentiation in the CNS. Various reports have shown excessive CSPG accumulation during CNS injuries and tumors [6,7,8]. CNS injuries have been documented to activate astrocytes and microglia to construct CS-rich glial scars, and the overproduced CSPGs are usually considered suppressors of the neurite outgrowths that impede neural rejuvenation [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
