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- W2980055991 abstract "Abstract Introduction The epigenetic regulator Bmi1 is essential for the self-renewal of neural stem cells (NSC), and highly expressed in glioblastoma (GBM) stem/initiating cells (GIC), where knockdown significantly reduces tumour growth in xenograft models. We have used a combined genome-wide and target gene-driven approach to identify EphrinA5 (EfnA5) as a mediator of Bmi1 function in mouse and human GIC. Methods and results We compared mGIC, from a PTEN/p53 deletion mouse model, to matched NSC. Combined ChIPSeq and RNASeq showed a differential redistribution of the repressive PRC mark H3K27me3 in mGIC, and that transcriptional regulation is Bmi1-dependent in a proportion of H3K27me3 marked genes. Subsequently, using shRNA knockdown, we show that Bmi1 regulates cell morphology, proliferation and migration/invasion via repression of EfnA5 in mGIC, and that the same mechanism is essential for GBM development in an allograft model. To confirm the translational potential of the BMI1/EFNA5 pathway we examined published RNA microarray, RNAseq and single-cell RNAseq datasets and found a significant inverse relationship between BMI1 and EFNA5. Finally, we show that BMI1 also regulates cell proliferation via repression of EFNA5 in primary human GIC in vitro. Conclusions We present evidence from a mouse model, human expression datasets and human primary cells showing that the Bmi1-EfnA5 pathway plays a prominent regulatory role in GIC. As the anti-proliferative role of BMI1 silencing is mediated by de-repression of EFNA5 in hGIC, precision targeting of Ephrin signalling, for example with agents that mimic EFNA5 action, could be an effective therapeutic tool in human GBM overexpressing BMI1." @default.
- W2980055991 created "2019-10-18" @default.
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- W2980055991 date "2019-10-01" @default.
- W2980055991 modified "2023-09-28" @default.
- W2980055991 title "Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma" @default.
- W2980055991 doi "https://doi.org/10.1093/neuonc/noz167.004" @default.
- W2980055991 hasPublicationYear "2019" @default.
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