Role of SIX5-mediated EXO1 overexpression in driving glioblastoma progression: Insights into tumor cell migration and angiogenesis

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, characterized by high recurrence and resistance to standard treatments, underscoring the pressing need for more effective and targeted therapeutic strategies. This study delved into the roles of sine oculis homeobox homolog 5 (SIX5) and exonuclease 1 (EXO1) genes in GBM pathogenesis and their potential as therapeutic targets. Through a comprehensive approach, utilizing bioinformatics analysis and experimental assays, we uncovered crucial insights. Firstly, high expression of EXO1 within GBM tissues was identified. Functional analyses following EXO1 knockdown revealed significant suppression of GBM cell viability, proliferation, migration, invasion, and induced DNA fragmentation. Notably, the suppression of EXO1 effectively hindered tumor growth in a subcutaneous xenograft model. Furthermore, our investigation highlighted SIX5 as an upstream regulator of EXO1. We elucidated the transcriptional relationship within the SIX5/EXO1 axis in GBM cells through ChIP experiments and dual-luciferase reporter gene assays. Intriguingly, the downregulation of SIX5 exhibited inhibitory effects on GBM cell growth in vitro, which were partially reversed by the overexpression of EXO1. In conclusion, the interplay between SIX5 and EXO1 emerges as a critical axis driving GBM development, shedding light on potential mechanisms for targeted interventions in combating this aggressive malignancy.