代谢调控表观基因组驱动致命性婴儿室管膜瘤。
Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.
机构信息
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
出版信息
Cell. 2020 Jun 11;181(6):1329-1345.e24. doi: 10.1016/j.cell.2020.04.047. Epub 2020 May 22.
Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
后颅窝 A 区（PFA）室管膜瘤是婴儿和幼儿后脑干的致命性恶性肿瘤。由于缺乏高度反复出现的体细胞突变，PFA 室管膜瘤被认为是受表观遗传驱动的肿瘤，但缺乏模型系统。在这里，我们证明 PFA 室管膜瘤在缺氧条件下得以维持，这与特定代谢物的有限可用性有关，这些代谢物可减少组蛋白甲基化，并增加组蛋白 3 赖氨酸 27（H3K27）的组蛋白去甲基化和乙酰化。PFA 室管膜瘤起源于人类发育第一个三个月中位于有限氧气环境中的细胞谱系。与其他室管膜瘤不同，PFA 细胞短暂暴露于环境氧中会引起不可逆的细胞毒性。PFA 肿瘤表现出低水平的 H3K27me3，矛盾的是，抑制 H3K27 甲基化特异性地破坏了 PFA 肿瘤的生长。针对代谢和/或表观基因组为患有 PFA 室管膜瘤的婴儿提供了合理治疗的独特机会。
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