TMBIM1 promotes epithelial mesenchymal transition by accelerating autophagic degradation of E-cadherin in glioblastoma.

Glioblastoma (GBM; WHO grade IV) is well known for its highly aggressive and recurrent nature and accounts for approximately 50% of all gliomas. Dysregulation of epithelial-mesenchymal transition (EMT) can lead to malignant progression of GBM. Therefore, it is an urgent need to delineate the mechanisms by which molecular drivers affect EMT in GBM. We found for the first time that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) was overexpressed in GBM tissues compared with nontumor brain tissues and that its expression level was correlated with the degree of malignancy of glioma. Patients with high TMBIM1 expression had shorter overall survival times than those with low TMBIM1 expression. Importantly, TMBIM1 induced EMT and autophagy, and inhibition of autophagy reversed TMBIM1-induced EMT in both in vitro and in vivo assays. TMBIM1 induced EMT by downregulating E-cadherin expression, which mediated by in-habitation of autophagic degradation of E-cadherin. Inhibition of TMBIM1 expression dramatically decreased the levels of p-AMPKα Thr172 and p-ULK1 Ser317 in U87 and U251 cells and increased the level of p-mTOR Ser2448. In addition, inhibition of AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin)/ULK1 (unc-51-like autophagy-activating kinase 1) axis partially attenuated TMBIM1-induced autophagy. Our study provides a novel mechanism for the regulation of EMT in the process of GBM invasion and migration, indicating that suppression of TMBIM1 activity to attenuate autophagy may be a potential strategy for the treatment of GBM.