Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44106, USA.
Cell Death Differ. 2012 Mar;19(3):428-39. doi: 10.1038/cdd.2011.109. Epub 2011 Aug 12.
Normal stem cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic stem cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia-inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and also contains high degrees of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. Recent experimental evidence has supported the importance of hypoxia in glioma stem cell (GSC) niches. We hypothesized that HIFs require epigenetic-modifying proteins to promote tumor malignancy in GBM. Here we demonstrate that in GBM the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia and enhances hypoxic responses. Loss of MLL1 reduces the expression of HIF transcripts and HIF2α protein. Targeting MLL1 by RNA interference inhibited the expression of HIF2α and target genes, including vascular endothelial growth factor (VEGF). GSCs expressed higher levels of MLL1 than matched non-stem tumor cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism mediating tumor hypoxic responses linking microenvironmental regulation of epigenetic-modifying proteins to cellular heterogeneity and provide rationale for the design of more sophisticated clinical approaches targeting epigenetic regulation.
正常的干细胞位于对自我更新和维持至关重要的功能龛中。神经和造血干细胞龛，特别是，其特点是氧气供应受限，由此导致缺氧诱导因子 (HIFs) 的调节。多形性胶质母细胞瘤 (GBM) 是最常见的恶性脑肿瘤，也包含高度缺氧。GBM 中已经很好地描述了肿瘤区室的异质性，并且可能源自在恶性进展过程中共同进化的遗传和表观遗传来源。最近的实验证据支持了缺氧在神经胶质瘤干细胞 (GSC) 龛中的重要性。我们假设 HIFs 需要表观遗传修饰蛋白来促进 GBM 中的肿瘤恶性程度。在这里，我们证明在 GBM 中，组蛋白甲基转移酶混合谱系白血病 1 (MLL1) 由缺氧诱导，并增强缺氧反应。MLL1 的缺失降低了 HIF 转录物和 HIF2α 蛋白的表达。通过 RNA 干扰靶向 MLL1 抑制了 HIF2α 和靶基因的表达，包括血管内皮生长因子 (VEGF)。GSCs 表达的 MLL1 水平高于匹配的非干细胞肿瘤细胞，并且 MLL1 的耗竭降低了 GSC 的自我更新、生长和致瘤性。这些研究揭示了一种介导肿瘤缺氧反应的新机制，将表观遗传修饰蛋白的微环境调节与细胞异质性联系起来，并为设计更复杂的靶向表观遗传调控的临床方法提供了依据。
