DLD, upregulated by YY1, fuels glioblastoma multiforme progression via EphA2 phosphorylation to activate PI3K/AKT/mTOR

BACKGROUND: Glioblastoma multiforme (GBM) is an incurable malignancy characterized by invasiveness and resistance to treatment. Dihydrolipoamide dehydrogenase (DLD), a metabolic redox enzyme, plays a pivotal role in key metabolic processes. Recent studies have increasingly highlighted the involvement of DLD in various cancers; however, its role in GBM remains underexplored. AIM: This study aimed to delineate the expression, regulation, and oncogenic function of DLD in glioma. METHODS: Expression analysis of DLD in GBM tissues, in vitro and in vivo functional assays, and mechanistic studies focusing on transcriptional regulation by YY1/EP300 and lncRNA CRNDE, as well as DLD-EphA2 interaction and PI3K/AKT/mTOR signaling. RESULTS: This study reveals that DLD is aberrantly overexpressed in GBM, with its expression level negatively correlating with clinical prognosis in patients with GBM. Both in vitro and in vivo analyses confirm that DLD acts as an oncogene in GBM, promoting cell proliferation, migration, and invasion. Mechanistically, DLD expression is regulated by the transcription factor YY1, with the coactivator EP300 interacting with YY1 to further enhance DLD expression. Moreover, the long non-coding RNA CRNDE facilitates YY1-EP300 interaction, thereby promoting DLD transcription. DLD also directly interacts with EphA2, influencing its phosphorylation at the S897 site and modulating the PI3K/AKT/mTOR pathway, which in turn supports its biological activities in GBM. CONCLUSIONS: DLD functions as an oncogene in GBM and represents a potential biomarker and therapeutic target.