MEK5-ERK5 Axis Promotes Self-renewal and Tumorigenicity of Glioma Stem Cells.

UNLABELLED

Glioma stem cells (GSC) promote the malignancy of glioblastoma (GBM), the most lethal brain tumor. ERK5 belongs to the MAPK family. Here, we demonstrated that MAPK kinase 5 (MEK5)-ERK5-STAT3 pathway plays an essential role in maintaining GSC stemness and tumorigenicity by integrating genetic and pharmacologic manipulation and RNA sequencing analysis of clinical specimens. ERK5 was highly expressed and activated in GSCs. silencing by short hairpin RNA in GSCs suppressed the self-renewal potential and GBM malignant growth concomitant with downregulation of STAT3 phosphorylation. Conversely, the activation of the MEK5-ERK5 pathway by introducing or resulted in increased GSC stemness. The introduction of STAT3 counteracted the GSC phenotypes by silencing. Moreover, ERK5 expression and signaling are associated with poor prognosis in patients with GBM with high stem cell properties. Finally, pharmacologic inhibition of ERK5 significantly inhibited GSC self-renewal and GBM growth. Collectively, these findings uncover a crucial role of the MEK5-ERK5-STAT3 pathway in maintaining GSC phenotypes and GBM malignant growth, thereby providing a potential target for GSC-directed therapy.

SIGNIFICANCE

In this study, we demonstrated that MEK5-ERK5-STAT3 axis plays a critical role in maintaining stemness and tumorigenicity in GSCs by using genetic, pharmacologic, and bioinformatics tools, identifying the MEK5-ERK5-STAT3 axis as a potential target for GSC-directed therapy.