LncRNA BDNF-AS binds to DNMT1 to suppress angiogenesis in glioma by promoting NEDD4L-mediated YAP1 ubiquitination

Glioma, a highly aggressive brain tumor, is characterized by high mortality and frequent recurrence rates. Angiogenesis is a critical hallmark of glioma progression. However, the regulatory role and underlying mechanism of lncRNA brain-derived neurotrophic factor-antisense (BDNF-AS) in glioma angiogenesis remain poorly understood and warrant further investigation. Malignant characteristics of glioma cells were evaluated using CCK-8, colony formation, scratch, transwell, flow cytometry, and tube formation assays. The expression levels of genes and proteins were detected by RT-qPCR, western blot, and IHC assays. The methylation level of NEDD4-like E3 ubiquitin protein Ligase (NEDD4L) was determined using MSP. The interactions among molecules were validated using RIP, ChIP, and Co-IP. Our study revealed significantly downregulated BDNF-AS expression in glioma cells. BDNF-AS overexpression markedly attenuated the malignant characteristics of glioma cells, as evidenced by decreased viability, proliferation, migration, invasion, and angiogenesis, along with increased Apoptosis. These tumor-suppressive effects were significantly abrogated by NEDD4L knockdown. Mechanistically, BDNF-AS could interact with DNA Methyltransferase 1 (DNMT1) expression, leading to reduced NEDD4L promoter methylation and upregulation of NEDD4L expression. Additionally, NEDD4L-mediated promotion of YAP1 ubiquitination to decline YAP1 and VEGFA expression. Finally, BDNF-AS exerted potent anti-tumor effects by mediating NEDD4L/YAP1/VEGFA axis, as demonstrated by suppressed tumor growth in glioma-bearing mice and attenuated malignant features in glioma cells. BDNF-AS suppressed cell viability, proliferation, migration, and invasion, and promoted cell Apoptosis of glioma cells, attenuated angiogenesis of human umbilical vein endothelial cells (HUVECs), and tumor growth via regulating NEDD4L/YAP1/VEGFA axis.

Angiogenesis; BDNF-AS; Glioma; NEDD4L; VEGFA; YAP1.