Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition.
Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition.
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DOI：
10.1158/0008-5472.can-21-0871
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发表时间：
2022-05-16
期刊：
影响因子：
11.2
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中科院分区：
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根据遗传、表观遗传和转录特征分析，髓母细胞瘤可分为四个亚组。放射治疗用于治疗成神经管细胞瘤，而不考虑亚组。更好地了解决定放射治疗反应的分子途径有助于改善髓母细胞瘤的治疗。在这里，我们研究了EZH 2依赖性组蛋白H3 K27三甲基化在髓母细胞瘤放疗反应中的作用。第3组和第4组髓母细胞瘤中47.2%的肿瘤显示H3 K27 me 3缺陷。H3 K27 me 3的缺失与放射抗性表型、高复发率和较差的总体存活率相关。在H3 K27 me 3缺陷型髓母细胞瘤细胞中，从H3 K27 me 3到H3 K27 ac的表观遗传转换发生在特定的基因组位点，改变了转录谱。由此产生的EPHA 2上调刺激了促存活AKT信号通路的过度激活，导致放射治疗抗性。BET抑制通过抑制H3 K27 ac水平、钝化EPHA 2过表达和减轻过度的AKT信号传导来克服H3 K27 me 3缺陷型髓母细胞瘤细胞中的辐射抗性。此外，BET抑制通过抑制Bcl-xL和上调Bim来增强凋亡反应，从而使髓母细胞瘤细胞对辐射敏感。这项工作证明了髓母细胞瘤放射抵抗的新机制，并确定了预测放射治疗反应的表观遗传标记。基于这些发现，我们提出了一种针对髓母细胞瘤患者放疗抵抗的表观遗传学指导治疗方法。
Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic, and transcriptional profiling. Radiation is used for treating medulloblastoma regardless of the subgroup. A better understanding of the molecular pathways determining radiotherapy response could help improve medulloblastoma treatment. Here, we investigated the role of the EZH2-dependent histone H3K27 trimethylation in radiotherapy response in medulloblastoma. The tumors in 47.2% of group 3 and 4 medulloblastoma patients displayed H3K27me3 deficiency. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates, and poor overall survival. In H3K27me3-deficient medulloblastoma cells, an epigenetic switch from H3K27me3 to H3K27ac occurred at specific genomic loci, altering the transcriptional profile. The resulting upregulation of EPHA2 stimulated excessive activation of the pro-survival AKT signaling pathway, leading to radiotherapy resistance. BET inhibition overcame radiation resistance in H3K27me3-deficient medulloblastoma cells by suppressing H3K27ac levels, blunting EPHA2 overexpression, and mitigating excessive AKT signaling. Additionally, BET inhibition sensitized medulloblastoma cells to radiation by enhancing the apoptotic response through suppression of Bcl-xL and upregulation of Bim. This 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 treatment approach targeting radiotherapy resistance in medulloblastoma patients.