Stmc-16. ezh2-mediated arl13b regulate ciliogenesis in gbm

Glioblastoma stem cells (GSCs) are known to be responsible for GBM therapeutic resistance. Previously we have reported exceptional plasticity within GBM during chemotherapy, which is associated with increases in GSC subpopulations. The Initial investigation indicated that Polycomb group protein EZH2 is critical for therapeutic stress-induced cellular plasticity. Chemical inhibition, as well as shRNA-mediated knockdown of EZH2, suppresses cellular plasticity-mediated increases in GSCs. To elucidate molecular mechanisms of EZH2-mediated therapeutic resistance, gene expression analysis was performed in the presence of the EZH2 inhibitor DZNep. The results indicate that the expression of ARL13B, a member of the ADP-ribosylation factor-like family protein critical for cilia formation and maintenance, was most affected by DZNep (more than 13-fold decreased). Knockdown of EZH2 by shRNA completely abolished the expression of ARL13B. TCGA data analysis revealed that ARL13b expression was inversely correlated with survival of patients with grade III (p=0.03) and IV GBM (p=0.007). Immunofluorescent staining showed that ARL13B co-localizes with cilium in primary GBM cells, as well as in a patient-derived xenograft (PDX) model. Chemotherapeutic stress on PDX models significantly enhanced formation (2 fold, p-value <0.0002) and length of primary cilium (1.5 fold, p-value <0.0001), as well as in post-therapy recurrent GBM PDX GBMs (3 fold, p-value <0.0005). Moreover, Shh activators...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research