SUV39H1 regulates progression of pediatric diffuse high-grade gliomas through modulation of β-catenin/TCF4 levels

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Pediatric diffuse high-grade gliomas (pHGGs) are heterogeneous and infiltrative tumors with poor prognosis. Recent molecular characterization of pHGGs has revealed an altered epigenetic profile with aberrant post-translational modifications and increased histone 3 lysine 9 trimethylation (H3K9) to be implicated in their pathology. Herein, we investigate the expression and biological role of the methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) in regulating key cancer hallmarks, including cell proliferation, motility, and epithelial-mesenchymal transition (EMT) gene regulation of pHGG. Bioinformatic analysis of SUV39H1 mRNA levels was performed in a public database of pediatric gliomas with respective controls. SUV39H1 protein expression was further investigated in a cohort of 24 pHGG tissues and controls by immunohistochemistry and western immunoblotting, followed by correlation analysis with patients' clinicopathological features. Gene silencing of SUV39H1 was performed in patient-derived pHGG cell lines (SJ-GBM2 and CHLA-200) to investigate their functional role in cell proliferation, migration, cell adhesion, and EMT markers. SUV39H1 mRNA was found enriched in pHGG tissues compared to normal brain, with pathway analyses (GO and KEGG) revealing a significant correlation with cell adhesion and focal adhesion pathways in SUV39H1-high pHGG. Immunohistochemical analysis of the pHGG cohort detected significantly increased SUV39H1 protein expression in pHGG tissues, followed by elevated H3K9me3 expression compared to normal brain tissues. Moreover, SUV39H1 and H3K9me3 levels were higher in pHGG with H3K27M mutation compared to H3-WT tumors and correlated with worst patients' survival. Gene silencing of SUV39H1 in SJ-GBM2 and CHLA-200 cells induced a significant decrease in cell viability and cell migration, followed by reduced expression of vimentin, β-catenin, and TCF4 protein levels. Furthermore, SUV39H1 silencing reduced the mRNA levels of EMT marker genes CDH2, SNAI1, and MARCKS. Our findings demonstrate that SUV39H1 regulates cell proliferation and adhesion in pHGG, contributing to epithelial-mesenchymal transition through regulation of β-catenin/TCF4 axis, presenting a promising therapeutic target to be investigated further. KEY MESSAGES: SUV39H1 gene expression is enriched in pHGG compared to normal brain. SUV39H1 expression is increased in pHGG tissues along with H3K9me3 expression. Gene silencing of SUV39H1 reduces cell viability and migration. SUV39H1 silencing decreased expression of vimentin, β-catenin and TCF4. SUV39H1 silencing reduced EMT marker genes CDH2, SNAI1 and MARCKS. SUV39H1 has an oncogenic role in pHGG and presents a promising therapeutic target.

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