Chondroitin sulfate synthase 1 enhances proliferation of glioblastoma by modulating PDGFRA stability

Abstract

Chondroitin sulfate synthases, a family of enzyme involved in chondroitin sulfate (CS) polymerization, are dysregulated in various human malignancies, but their roles in glioma remain unclear. We performed database analysis and immunohistochemistry on human glioma tissue, to demonstrate that the expression of CHSY1 was frequently upregulated in glioma, and that it was associated with adverse clinicopathologic features, including high tumor grade and poor survival. Using a chondroitin sulfate-specific antibody, we showed that the expression of CHSY1 was significantly associated with CS formation in glioma tissue and cells. In addition, overexpression of CHSY1 in glioma cells enhanced cell viability and orthotopic tumor growth, whereas CHSY1 silencing suppressed malignant growth. Mechanistic investigations revealed that CHSY1 selectively regulates PDGFRA activation and PDGF-induced signaling in glioma cells by stabilizing PDGFRA protein levels. Inhibiting PDGFR activity with crenolanib decreased CHSY1induced malignant characteristics of GL261 cells and prolonged survival in an orthotopic mouse model of glioma, which underlines the critical role of PDGFRA in mediating the effects of CHSY1. Taken together, these results provide information on CHSY1 expression and its role in glioma progression, and highlight novel insights into the significance of CHSY1 in PDGFRA signaling. Thus, our findings point to new molecular targets for glioma treatment.

Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin β1 Expression

“…We have previously demonstrated that 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 ]. Thus, to explore the CS-associated pathways in human GBM, we analyzed genes co-expressed with CHSY1 in the TCGA dataset using the cBioPortal for cancer genomics [ 33 ].…”

“…Our previous studies have identified that CHSY1 is frequently upregulated in tumor tissues such as human glioma and hepatocellular carcinoma. Moreover, the upregulation of CHSY1 not only enhances CS formation on cancer cells, but is also positively associated with poor patient outcomes [ 16 , 17 ]. However, the specific CSPGs involved in the CHSY1-regulated malignant phenotypes of cancer cells are yet to be explored.…”

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-β Pathways

“…Importantly, using the TGF-β type I receptor kinase inhibitor, LY364947 successfully reversed CHPF-silencing-enhanced cell viability, cell migration, and invasion (Figure 5B,C), suggesting that TGF-β signaling participates in CHPF-regulated malignancy of HCC cells. CS synthases-remodeled CS proteoglycans (CSPGs) are crucial for modulating signal transduction and cell-cell communication [21,23,34], and CSPG DCN is known to be a key regulator of TGF-β signaling [35][36][37]. Thus, we examined the influence of CHPF on DCN in HCC cells.…”

“…Several recent studies have revealed that these CS synthases and CS-modifying enzymes show tissue-specific expression profiles and play distinct roles in regulating the malignant behaviors of cancer cells. For instance, CHSY1 was upregulated in HCC and glioma tissues, and its upregulation was associated with poor outcomes in patients [20,21]. The CS epimerase DSE is also frequently upregulated in human gliomas, and its increased expression is typically associated with worse prognoses [22].…”

Long intergenic noncoding RNA00265 promotes proliferation of gastric cancer via the microRNA-144-3p/Chromobox 4 axis

“…Besides, a recent study indicated that lncRNA PVT1 was highly expressed in GC tissues and can promote tumor progression by interacting with FoxM1, and PVT1 [ 18 ]. Furthermore, Xiao et al reported that lncRNA TRPM2-AS exerted a pro-tumor effect by sponging miR-612 in GC cells [ 19 ]. In addition, there are many other dysregulated lncRNAs involved in GC progression, such as LINC00152, PANDA, MAGI2-AS3, PWRN1 and TUBA4B [ 20 ].…”