Glioblastoma multiforme (GBM) or
glioblastoma is the most deadly malignant
brain tumor in adults. GBM is difficult to treat mainly due to the presence of
glioblastoma stem cells (GSCs).
Epidermal growth factor receptor variant III (
EGFRvIII) has been linked to stemness and
malignancy of GSCs; however, the regulatory mechanism of
EGFRvIII is largely unknown. Here, we demonstrated that
Anoctamin-1 (ANO1), a Ca2+-activated Cl- channel, interacts with
EGFRvIII, increases its protein stability, and supports the maintenance of stemness and
tumor progression in GSCs. Specifically,
shRNA-mediated knockdown and pharmacological inhibition of ANO1 suppressed the self-renewal, invasion activities, and expression of
EGFRvIII and related stem cell factors, including NOTCH1,
nestin, and SOX2 in GSCs. Conversely, ANO1 overexpression enhanced the above phenomena. Mechanistically, ANO1 protected
EGFRvIII from proteasomal degradation by directly binding to it. ANO1 knockdown significantly increased survival in mice and strongly suppressed local invasion of GSCs in an in vivo intracranial mouse model. Collectively, these results suggest that ANO1 plays a crucial role in the maintenance of stemness and invasiveness of GSCs by regulating the expression of
EGFRvIII and related signaling molecules, and can be considered a promising therapeutic target for GBM treatment.