Abstract
Glioblastomas are highly lethal cancers that display cellular hierarchies with glioma stem cells (GSCs) at the apex. Targeting GSCs may provide improved tumor control, underscoring the need for improved understanding of their underlying biology. Inhibitor of differentiation 1 (ID1) promotes gliomagenesis through stimulation of GSC growth. We now report that ID1 controls GSCs through suppression of the E3 ligase, Cullin3. Cullin3 feedback suppression of ID1 simultaneously activates ligand-independent WNT and SHH signaling by increasing Dvl2 and Gli2 levels, respectively. Further, Cullin3 suppresses BMP signaling by attenuating BMPR2 through WNT-b-catenin-driven miR-17/-20a induction. The clinical relevance of these findings is supported by an in silico association of the ID1High/Cullin3Low gene expression signature in glioblastomas with the activation of multiple stem cell pathways. Simultaneous targeting of these core GSC pathways enhanced survival of GSC-bearing mice, supporting translation into a novel targeted therapy. Taken together, these findings suggest that Cullin3 represents a common signaling node controlling the activity of multiple essential GSC pathways mediated by ID1.
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