BET Inhibition Targets Radiation Resistance in H3K27me3-Deficient Medulloblastoma

Abstract

Medulloblastoma has been categorized into four subgroups based on genetic and epigenetic profiling. However, molecular pathways determining radiotherapy response in this tumor remain unknown. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiation response in medulloblastoma.We analyzed the H3K27me3 expression medulloblastoma tumor samples and determined the correlation between the H3K27me3 status and PFS and OS in 36 non-WNT/SHH medulloblastoma patients. We used an ex vivo mouse model of group 3 medulloblastoma to elucidate the molecular mechanism of radiation resistance in H3K27me3-deficient tumors and develop an approach to target radiotherapy resistance.We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at certain genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an over-activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibitors target radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression.Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided personalized treatment approach to target radiotherapy resistance in medulloblastoma patients.