BTSCs exosomes derived NamiRNA-enhancer network of miR-151a-3p mediates a positive feedback loop and promotes the progression of glioma via FAK phosphorylation.

Glioblastoma (GBM) is a highly invasive and treatment-resistant brain tumour, with recurrence often driven by the persistence of brain tumour stem cells (BTSCs). Recent evidence suggests that BTSC-derived exosomes, particularly under hypoxic conditions, play a critical role in GBM progression by facilitating intercellular communication and enhancing tumour invasiveness; however, the precise molecular mechanisms remain unclear. We demonstrated that hypoxic BTSCs (H-BTSCs) influence glioma cells through the transfer of exosomes. High-throughput sequencing revealed a marked increase in miR-151a-3p expression under hypoxic. Mechanistically, miR-151a-3p functions within a nuclear-activating miRNA (NamiRNA)-enhancer network: P300 acetylates PDE4D, and H3K27ac-dependent binding to the PDE4D promoter upregulates Focal Adhesion Kinase (FAK)/Yes-Associated Protein (YAP) signaling in GBM cells. CRISPR/Cas9-mediated deletion of the PDE4D enhancer confirmed that miR-151a-3p's function is enhancer dependent. Both in vitro and in vivo experiments demonstrated that exosomal miR-151a-3p promotes glioma cell migration, invasion, proliferation, and epithelial‒mesenchymal transition, thereby increasing tumour aggressiveness. These findings highlight the NamiR-151a-3p/PDE4D/FAK/YAP axis as a promising therapeutic target for GBM.