ELK4 induced upregulation of HOMER3 promotes the proliferation and metastasis in glioma via Wnt/β-catenin/EMT signaling pathway

Abstract

Glioma is an aggressive brain tumor characterized by its high invasiveness, which complicates prognosis and contributes to patient resistance against various treatment options. The HOMER family, consisting of HOMER1, HOMER2, and HOMER3, has been implicated in various cancers, yet their specific roles in glioma remain inadequately understood. This study conducted a comprehensive pan-cancer analysis to evaluate the expression profiles of HOMER family members across different tumor types, utilizing data from public databases such as TCGA and GTEx. Our findings indicate significant dysregulation of HOMER1, HOMER2, and HOMER3 in multiple cancers, with HOMER3 emerging as a potential prognostic biomarker, particularly for lower-grade glioma. Elevated expression levels of HOMER3 were associated with shorter overall survival and disease-specific survival in LGG patients, supported by Cox regression analysis that confirmed HOMER3 as an independent prognostic factor. Furthermore, HOMER3 expression correlated positively with advanced clinical stages and key tumor markers. To elucidate the mechanisms behind HOMER3 dysregulation, we identified ELK4 as a transcription factor that binds to the HOMER3 promoter, promoting its expression in glioma cells. Functional assays demonstrated that silencing HOMER3 significantly reduced glioma cell proliferation and metastatic potential in vitro and in vivo, highlighting its oncogenic role. Additionally, HOMER3 was found to influence the Wnt/β-catenin/EMT signaling pathway, with knockdown resulting in altered expression of critical EMT markers. Collectively, our results indicated that HOMER3 plays a crucial role in glioma progression and metastasis, underscoring its potential as a therapeutic target and prognostic biomarker in glioma management.