ERK5 regulates stemness and tumorigenicity of glioma stem cells by controlling the STAT3 signaling

Abstract

Glioblastoma (GBM), the most malignant form of primary brain tumor, has a very dismal prognosis. Glioma stem cells (GSCs) contribute to the initiation and progression of GBM. Extracellular signal-regulated kinase 5 (ERK5) has been shown to regulate tumorigenicity, metastasis and drug resistance of cancer stem cells (CSCs). However, the functional role and underlying mechanisms of ERK5 expressed in GSCs on gliomagenesis are still poorly understood in vitro and in vivo. Silencing ERK5 by shRNA significantly attenuated the self-renewal potential and tumorigenicity of patient-derived GSCs, which can be rescued by the overexpression of STAT3. In addition, the pharmacological inhibition of ERK5 significantly suppressed the self-renewal potential and tumorigenicity of GSCs. Bioinformatics analyses demonstrated that ERK5 expression was significantly higher in human GBM tissues, and ERK5 pathway was positively regulated in GSCs. Moreover, ERK5 expression was associated with poor survival in GBM patients. These results highlight the importance of the ERK5-STAT3 axis in maintaining stemness and tumorigenicity in GSCs, thereby demonstrating a potential target for GSC-directed therapy.