CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability

The methyl transferase METTL3 is up-regulated in brain tumors leading to the methylation of CPEB2 mRNA, which in turn stabilizes the splicing factor SRSF5 mRNA, leading to the incorporation of exon 7 in ETS-1 in models of the Blood-Tumor Barrier. The blood-tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood-brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.

Automated summary

The up-regulation of methyl transferase METTL3 in brain tumors leads to the methylation of CPEB2 mRNA, which stabilizes the splicing factor SRSF5 mRNA and promotes the inclusion of exon 7 in ETS-1. Both in vitro and in vivo experiments demonstrate that this process can increase the permeability of the blood-tumor barrier (BTB), enhance drug penetration, and improve glioma-specific chemotherapeutic effects.