# Tumor-suppressive activities of SA1/STAG2 and effects of PARP impairment during brain development

## TL;DR

This study shows that STAG2/SA1 acts as a tumor suppressor in brain development and that PARP inhibition can counteract its loss, offering a potential treatment for brain tumors.

## Contribution

The study identifies STAG2/SA1 as a tumor suppressor in brain development and reveals that PARP inhibition can reverse its loss effects.

## Key findings

- STAG2 variants are found in glioblastoma and medulloblastoma patients.
- Loss of SA1 in Drosophila leads to neural stem cell differentiation defects and tumorigenesis.
- PARP inhibition combined with SA1/STAG2 depletion induces apoptosis in tumor cells.

## Abstract

The cohesin complex performs essential cellular functions including regulation of chromatin organization and DNA repair. Somatic pathogenetic variants in cohesin genes, such as STAG2, have been associated with cancer, but their contribution to brain tumorigenesis is unclear. Here, we report the presence of STAG2 variants in patients with glioblastoma and medulloblastoma and determined the effects of loss of STAG2 in human cells and of the homolog SA1 in Drosophila tissues. Reduction of SA1 expression during fly brain development led to defects in neural stem cell differentiation and promotion of tumorigenesis, both in the presence and absence of oncogenic activity. Treatment with inhibitors of poly ADP-ribose polymerase (PARP), which are used to treat forms of cancer with defects in DNA repair, in combination with STAG2/SA1 depletion resulted in apoptosis in vitro and in vivo. In flies, reduction of PARP activity ameliorated the tumor-associated phenotypes of SA1-deficient tissue. Our in vivo and in vitro data suggest that impairment of PARP activity compensates for reduced cohesin activity, highlighting a vulnerability that could be pharmacologically exploited in brain tumors.

Summary: In Drosophila melanogaster and in human cells, SA1/STAG2 acts as a tumor suppressor and PARP inhibition reverts the tumor-associated effects of reducing SA1/STAG2 expression during brain development and tumorigenesis.