Hypermethylation of Sox21 masks its oncogenic role in glioblastoma

The transcription factor Sox21, a member of the SRY-related HMG-box (SOX) family, is known to promote neuronal differentiation and regulate stem cell function; however, its role in brain tumors remains largely unexplored. Because epigenetic dysregulation contributes to aberrant gene expression and malignant progression, we aimed to elucidate the expression and function of Sox21 in U87 human glioblastoma cells. A marked reduction in Sox21 mRNA and protein expression was observed by RT-PCR and Western blot analysis. Methylation-specific PCR (MSP) and bisulfite sequencing further revealed that the Sox21 promoter is hypermethylated, indicating that Sox21 expression is epigenetically regulated in U87 cells.To determine the functional consequences of restoring Sox21, U87 cells were transfected with a Sox21-expressing vector, resulting in a robust increase in Sox21 expression. Forced Sox21 expression significantly enhanced cell proliferation, as shown by MTT assays and flow cytometry, and was accompanied by a decreased proportion of cells in the sub-G1 phase, suggesting a growth-promoting role for Sox21 in glioblastoma cells. In addition, Sox21 overexpression accelerated cell migration, as demonstrated by wound-healing and transwell assays.These findings indicate that Sox21 downregulation in glioblastoma is mediated, at least in part, by promoter hypermethylation. However, restoring its expression facilitates tumor cell growth and migration. Collectively, our results demonstrate that Sox21 functions as an oncogene that is epigenetically silenced through promoter hypermethylation in glioblastoma.