SOX21 suppresses GBM growth by repressing AP-1 regulated target genes
BackgroundTreatment-resistant glioblastoma stem cells (GSCs) drive glioblastoma (GBM) growth and recurrence. Thus, targeting the molecular machinery that sustains GSCs in an undifferentiated and self-renewing state is a promising therapeutic strategy. The transcription factor SOX21 effectively suppresses the tumorigenic capacity of GSCs. However, the mechanism by which SOX21 impedes GSC features is unknown. MethodsPatient-derived GSCs were engineered with a transgenic TetOn system to enable inducible expression of SOX21 or appropriate controls. The capacity of SOX21 to incapacitate GSCs was assessed using in vitro cell culture models and orthotopic mouse models. Cellular and genome-wide techniques, including RNA-seq, ChIP-seq, and ATAC-seq, were employed to examine the mechanisms by which SOX21 regulates GSCs. ResultsWe show that SOX21 expression in primary GSCs induces an anti-tumorigenic transcriptional program, aligning with clinical data showing a positive correlation between SOX21 levels and improved GBM patient survival. Induced SOX21 expression in GSCs within pre-established GBM reduces their capacity to sustain tumor growth and significantly extends the survival of the transplanted mice. Mechanistically, SOX21 functions as a tumor suppressor by binding a large set of AP-1-targeted chromatin regions, leading to epigenetic repression of AP-1-activated genes that support GSC survival and proliferation. Consistently, the anti-tumorigenic activities of SOX21 are replicated by AP-1 inhibitors, while overexpression of the AP-1 family member, c-JUN, counteracts these effects. ConclusionOur findings identify SOX21 as a key regulator that prevents GSC malignancy by targeting and repressing an AP-1-driven, tumor-promoting gene expression program. These results highlight SOX21-regulated pathways as promising therapeutic targets for GBM. Key PointsO_LIInduced SOX21 expression suppresses GSCs and inhibits the growth of established GBM C_LIO_LISOX21 acts as a tumor suppressor in GSCs by directly repressing AP-1-driven genes C_LIO_LIPharmacological inhibition of AP-1 mimics SOX21 activity in GSCs C_LI Importance of the StudyGBM is the most common and aggressive malignant brain tumor in adults. Recurrence following treatment often stems from the failure of therapeutic interventions to effectively target GSCs, which serve as the primary reservoir for tumor regrowth. The resilience of GSCs to treatment is partly due to the inactivation of intrinsic tumor suppressor programs that would otherwise direct GSCs to cellular senescence and death. This study demonstrates that increased expression levels of the tumor suppressor SOX21 in pre-established GBM disrupt tumor progression by disabling self-renewing GSCs. We show that SOX21 exerts its tumor-suppressive function by targeting and repressing an AP-1-driven gene network, which is a key regulator of GSC maintenance and proliferation. By uncovering the molecular mechanisms through which SOX21 controls GSC biology, our findings provide valuable insights for basic cancer research and may inform the development of novel therapeutic strategies for GBM.