SOX21 suppresses GBM growth by repressing AP-1 regulated target genes

Abstract

AbstractResistance of glioblastoma stem cells (GSCs) to standard treatments is a major cause of glioblastoma (GBM) recurrence. This study examines the potential of the transcription factor SOX21 to inhibit GSC properties and combat GBM progression. Results show that increasing SOX21 levels in primary GSCs induces an anti-tumorigenic gene expression profile, which is substantiated by a significant correlation between high SOX21 expression and improved survival rates of GBM patients. Furthermore, induced SOX21 expression in pre-established GBM reduces tumor growth and significantly extends the survival of orthotopically transplanted mice. SOX21 acts as a tumor suppressor by binding to and epigenetically repressing AP-1-targeted chromatin, thereby downregulating adjacent genes. Consistently, the anti-tumorigenic activities of SOX21 are replicated by small molecules that inhibit AP-1 activity, whereas overexpression of an AP-1 transcription factor reverses these effects. Overall, this research demonstrates the potent role of SOX21 in restricting GBM progression through repression of AP-1-stimulated tumor-promoting gene expression.