THOC1 complexes with SIN3A to regulate R-loops and promote glioblastoma progression.

Abstract

Glioblastoma (GBM), the most common and aggressive primary malignant brain tumor in adults, has a median survival of 14.6 months. To identify drivers of GBM pathogenesis, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous neural stem cells bolstered transformation capacity, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1's interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. RNA-sequencing analysis revealed that THOC1's role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 is a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential. STATEMENT OF SIGNIFICANCE: Glioblastoma, the most aggressive malignant brain tumor in adults, relies on a delicate R-loop landscape to promote cell replication while avoiding DNA damage. Targeting THOC1 represents a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.