Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine, Emory University, Atlanta, GA, 30322, USA.
Department of Neurosurgery, Xiangya Hospital and School of Medicine, Central South University, 410013, Changsha, Hunan, P.R. China.
Oncogene. 2020 Jan;39(5):1041-1048. doi: 10.1038/s41388-019-1036-7. Epub 2019 Oct 3.
Medulloblastoma (MB) is a malignant pediatric brain tumor for which new therapies are urgently needed. We demonstrate that treatment with EPZ-6438 (Tazemetostat), an enhancer of zeste homolog 2 (EZH2) inhibitor approved for clinical trials, blocks MB cell growth in vitro and in vivo, and prolongs survival in orthotopic xenograft models. We show that the therapeutic effect is dependent on epigenetic reactivation of adhesion G-protein-coupled receptor B1 (BAI1/ADGRB1), a tumor suppressor that controls p53 stability by blocking Mdm2. Histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation is present at the ADGRB1 promoter, and inhibition of EZH2, the catalytic component of the Polycomb Repressive complex 2 (PRC2) that methylates H3K27, switches the gene into an active chromatin status and reactivates BAI1 expression. Mechanistically, targeting EZH2 promotes transition from H3K27me3 to H3K27ac at the promoter, recruits the C/EBPβ (CREB-binding protein) and CBP transcription factors and activates ADGRB1 gene transcription. Taken together, our results identify key molecular players that regulate ADGRB1 gene expression in MB, demonstrate that reactivation of BAI1 expression underlies EPZ-6438 antitumorigenic action, and provide preclinical proof-of-principle evidence for targeting EZH2 in patients with MB.
髓母细胞瘤（MB）是一种恶性小儿脑肿瘤，急需新的治疗方法。我们证明，用 EPZ-6438（Tazemetostat）治疗，一种已被批准用于临床试验的增强子外显子 2（EZH2）抑制剂，可阻断 MB 细胞的体外和体内生长，并延长原位异种移植模型中的存活时间。我们表明，治疗效果取决于黏附 G 蛋白偶联受体 B1（BAI1/ADGRB1）的表观遗传再激活，BAI1/ADGRB1 是一种肿瘤抑制因子，通过阻断 Mdm2 来控制 p53 的稳定性。组蛋白 3 在赖氨酸 27 上的三甲基化（H3K27me3）是沉默染色质构象的标志物，存在于 ADGRB1 启动子上，抑制 EZH2（Polycomb Repressive complex 2（PRC2）的催化亚基，使 H3K27 甲基化），可将基因转换为活跃的染色质状态并重新激活 BAI1 的表达。从机制上讲，靶向 EZH2 可促进启动子处的 H3K27me3 向 H3K27ac 的转变，募集 C/EBPβ（CREB 结合蛋白）和 CBP 转录因子，并激活 ADGRB1 基因转录。总之，我们的研究结果确定了调节 MB 中 ADGRB1 基因表达的关键分子，证明了 BAI1 表达的重新激活是 EPZ-6438 抗肿瘤作用的基础，并为在 MB 患者中靶向 EZH2 提供了临床前的原理证明。
