Glioblastoma (GBM) is the most aggressive brain tumor, with a strong invasiveness and high tolerance to chemotherapy. With the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma can be incurable due to drug resistance. The existence of glioma stem‐like cells (GSCs) is considered the major reason for drug resistance. However, the mechanism of GSC enrichment remains unclear. Herein, we found that the expression and secretion of angiopoietin‐like 4 protein (ANGPTL4) were obviously increased in GSCs. The overexpression of ANGPTL4 induced GSC enrichment that was characterized by BMI‐1 and SOX2 expression, resulting in TMZ resistance in GBM. Furthermore, epidermal growth factor (EGFR) phosphorylation induced 4E‐BP1 phosphorylation that was required for ANGPTL4‐induced GSC enrichment. In particular, ANGPTL4 induced 4E‐BP1 phosphorylation by activating PI3K/AKT and ERK cascades for inducing stemness. To elucidate the mechanism contributing to ANGPTL4 upregulation in GSCs, chromatin immunoprecipitation coupled with sequencing (ChIP‐Seq) revealed that specificity protein 4 (Sp4) associates with the promoter region, −979 to −606, and the luciferase reporter assay revealed that Sp4 positively regulates activity of the ANGPTL4 promoter. Moreover, both ANGPTL4 and Sp4 were highly expressed in GBM and resulted in a poor prognosis. Taken together, Sp4‐mediated ANGPTL4 upregulation induces GSC enrichment through the EGFR/AKT/4E‐BP1 cascade.
Date:
2020-04
Relation:
FASEB Journal. 2020 Apr;34(S1):Abstract number 02019.
