Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Cancer Cell. 2015 Dec 14;28(6):715-729. doi: 10.1016/j.ccell.2015.10.005. Epub 2015 Nov 25.
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
组蛋白 3 变体 H3.3 的突变已在三分之一的儿童脑胶质瘤（GBM）中被发现，但在成人肿瘤中未被发现。在这里，我们表明 H3.3 是成人 GBM 功能特性的动态决定因素。H3.3 被多谱系白血病 5（MLL5）在自我更新的 GBM 细胞中抑制。MLL5 是一种全局表观遗传抑制剂，通过在染色体上形成致密染色质的焦点来打断染色体结构的重组，从而促进肿瘤发生和自我更新特性。相反，H3.3 拮抗自我更新并促进分化。我们利用这些表观遗传状态，在临床前模型中合理地确定了两种能够有效抑制癌症干细胞特性的小分子。我们的工作揭示了 MLL5 和 H3.3 在维持成人 GBM 自我更新层次结构中的作用。
