In addition, we identified pivotal targets downstream of BMI1 in CD133+ cells such as integrin alpha 2 (ITGA2), that may contribute to regulating GBM stem cell properties.
Our work highlights the role of DHHC proteins in the plasticity of GBM subsets and reveals that BMI1 represents a potential therapeutic target for human gliomas.
Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation.
The overexpression of ANGPTL4 induced GSC enrichment that was characterized by polycomb complex protein BMI-1 and SRY (sex determining region Y)-box 2 (SOX2) expression, resulting in TMZ resistance in GBM.
Transcriptomic analyses of TCGA datasets of glioblastoma and PTC-209-treated GBM cells demonstrate that PTC-209 reverses the altered transcriptional program associated with BMI-1 overexpression.
Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.
Collectively, these findings indicate that loss of microRNA-16 may favor glioma angiogenesis, on the contrary overexpression of microRNA-16 in GBM cells plays a critical role in repressing endothelial function and angiogenesis by targeting Bmi-1. microRNA-16 may be a potential therapeutic agent in the treatment of GBM.
Overexpression of miR-130b induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF and the pluripotency associated markers, including CD133, SOX2, Nanog, MYC and BMI1, leading to promotion of glioblastoma stem cell phenotype.
In mouse and human neural progenitor and glioblastoma "stem-like" cells, we identified key targets of the Polycomb-group protein BMI1 by combining ChIP-seq with in vivo RNAi screening.
Bmi1 expression profiles show a marked elevation in the proneural GBM subtype, and stem cell frequency as assessed by tumor sphere assays correlates with patient outcome.
We found that overexpression of c-Myc was significantly associated with that of BMI1 (P = .009), and that patients who harbored glioblastomas overexpressing c-Myc and BMI1 showed significantly longer overall survival (P < .0001 and P = .0009, respectively).