Xiangya School of Medicine, Central South University, Changsha, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Nat Cell Biol. 2023 Mar;25(3):493-507. doi: 10.1038/s41556-023-01093-0. Epub 2023 Feb 27.
How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus. We further identify that a core set of transcription factors, enhancer of zeste homologue 2 (EZH2) and nuclear factor I X (NFIX), coordinates with the cis-regulatory elements at the SMARCD3 locus to form a chromatin hub to control SMARCD3 expression in the developing cerebellum and in metastatic MB. Increased SMARCD3 expression activates Reelin-DAB1-mediated Src kinase signalling, which results in a MB response to Src inhibition. These data deepen our understanding of how neurodevelopmental programming influences disease progression and provide a potential therapeutic option for patients with MB.
异常神经发育与成神经管细胞瘤（MB）的肿瘤侵袭性之间的关系仍不清楚，MB 是最常见的胚胎性肿瘤。在这里，我们揭示了一个被劫持的神经发育表观基因组程序，该程序可诱导 MB 转移扩散。对综合公开数据集和我们新生成的数据进行无监督分析表明，SMARCD3（也称为 BAF60C）通过在 DAB1 基因座上调控顺式调控元件来调节Disabled 1（DAB1）介导的 Reelin 信号在浦肯野细胞迁移和 MB 转移中的作用。我们进一步确定，一组核心转录因子，包括增强子结合因子 2（EZH2）和核因子 IX（NFIX），与 SMARCD3 基因座上的顺式调控元件协调，形成染色质枢纽，以控制发育中的小脑和转移性 MB 中的 SMARCD3 表达。SMARCD3 表达的增加激活了 Reelin-DAB1 介导的Src 激酶信号，导致 MB 对 Src 抑制的反应。这些数据加深了我们对神经发育编程如何影响疾病进展的理解，并为 MB 患者提供了一种潜在的治疗选择。
