# SOX21 suppresses glioblastoma growth by repressing AP-1 activity

## TL;DR

SOX21 stops glioblastoma growth by blocking AP-1 activity, which could lead to new treatments for this aggressive brain cancer.

## Contribution

SOX21 is identified as a tumor suppressor that represses AP-1-driven gene programs in glioblastoma stem cells.

## Key findings

- SOX21 expression reduces the tumorigenic capacity of glioblastoma stem cells.
- SOX21 represses AP-1-targeted chromatin regions, inhibiting tumor-promoting gene expression.
- AP-1 inhibitors replicate SOX21's anti-tumorigenic effects, suggesting a therapeutic strategy.

## Abstract

Treatment-resistant glioblastoma stem and precursor cells (GPCs) drive glioblastoma (GBM) growth and recurrence. Thus, targeting the molecular machinery that sustains GPCs in an undifferentiated and self-renewing state is a promising therapeutic strategy. The transcription factor SOX21 effectively suppresses the tumorigenic capacity of GPCs, but the mechanism by which SOX21 impedes GPC features is unknown. By engineering patient-derived GPCs with a transgenic TetOn system we show that SOX21 expression induces an anti-tumorigenic transcriptional program, aligning with clinical data demonstrating a positive correlation between SOX21 levels and improved GBM patient survival. Induced SOX21 expression in GPCs within pre-established GBM reduces their capacity to sustain tumor growth and significantly extends the survival of the orthotopically 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. Consistently, the anti-tumorigenic activities of SOX21 are largely replicated by AP-1 inhibitors, which decrease GPC proliferation and survival, while overexpression of the AP-1 family member, c-JUN, counteracts these effects. Our findings identify SOX21 as a key regulator that prevents GPC 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.