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Abstract
Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1.
Highlights
Malignant gliomas are the most common intrinsic brain tumours in adults
We have recently demonstrated that conditional overexpression of Bmi1 has a different functional impact on central nervous system (CNS) development depending on the differentiation stage of neural precursor cells [20], and that this is mediated by the amount of H3K27me3 at the promoter region of selected target genes in a cell-context-dependent fashion [21]
In order to define the cellular pathways deregulated in gliomagenesis in a Bmi1-dependent, H3K27me3-mediated manner, we used a well-established mouse model of gliomagenesis that relies on the loss of PTEN and p53, two of the most common genetic alterations in IDH wild-type glioblastoma (GBM) [23]
Summary
Malignant gliomas are the most common intrinsic brain tumours in adults. They grow highly invasively, cannot be completely resected by surgery, and conventional anticancer treatments have limited efficacy, resulting in a dismal overall prognosis. PRC1 depends upon PRC2 for recruitment to PcG target genes and is responsible for mono-ubiquitylation of histone H2A at lysine 119 (H2AK119u), an enzymatic activity dependent on the E3 ubiquitin ligase activity of Ring1B, which is enhanced by Bmi1 This sequence of events induces chromatin compaction and inhibition of transcription elongation (reviewed in [3]), alternative mechanisms of action have been described [4]. We have shown that GIC isolated from a mouse model of HGG [22] show a similar epigenetic regulation of Bmi target genes [21] These data are in keeping with increased H3K27me being a general mechanism mediating the functional outcome of elevated Bmi expression in both non-neoplastic and neoplastic contexts. The availability of nonneoplastic NSC engineered to overexpress Bmi allowed us to mimic the physiological fluctuation of Bmi expression during neural differentiation
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