LAMTOR5 Drives Glioblastoma Progression via Activation of the HOXC9/YTHDF2 Positive Feedback Loop

Glioblastoma is the most aggressive primary malignant brain tumor in adults, characterized by high invasiveness and poor prognosis. The knowledge of driver genes and prognostic markers predictive of poor outcomes in glioblastoma is still limited. In the current manuscript, we show that LAMTOR5 is a driver gene for glioblastoma progression through transcriptionally activating the HOXC9/YTHDF2 positive feedback loop. LAMTOR5 is highly expressed in glioblastoma, predicts poor prognosis in glioma patients and is essential for the growth, invasion and tumorigenesis of glioblastoma cells. Using a bioinformatics analysis approach based on multiple public datasets, we identified YTHDF2 as a downstream effector of LAMTOR5. LAMTOR5 promotes the expression of YTHDF2 through increasing its promoter activity by coactivating the transcription factor HOXC9. In turn, the LAMTOR5-upregulated YTHDF2 enhances the expression of HOXC9 through promoting the mRNA stability of HOXC9 in an m⁶A-dependent manner, forming a positive feedback loop in LAMTOR5-overexpressed glioblastoma cells. Silencing YTHDF2 can abrogate the LAMTOR5-promoted proliferation and invasion of glioma cells both in vitro and in vivo. Thus, we conclude that LAMTOR5 is an oncogenic protein driving glioblastoma progression via activating the HOXC9/YTHDF2 positive feedback loop. Our results offer new insights into the regulatory interplay between transcription and m⁶A modification of oncogenic proteins in glioblastoma and provide a therapeutic target for glioblastoma treatment.