双功能 LSD1/HDAC 抑制剂重编程染色质可诱导 DIPG 治疗性分化。
Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.
机构信息
Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Womens Hospital, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2019 Nov 11;36(5):528-544.e10. doi: 10.1016/j.ccell.2019.09.005. Epub 2019 Oct 17.
H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.
导致表观遗传功能障碍的 H3K27M 突变在弥漫性内在脑桥胶质瘤（DIPG）中频繁观察到，这是一种无法治愈的儿科癌症。我们进行了一项 CRISPR 筛选，结果表明，编码赖氨酸特异性去甲基酶 1（LSD1）的 KDM1A 的敲除使 DIPG 细胞对组蛋白去乙酰化酶（HDAC）抑制剂敏感。一致地，Corin，一种 HDAC 和 LSD1 的双功能抑制剂，在体外和异种移植中有力地抑制了 DIPG 的生长。在机制上，Corin 增加了被 H3K27M 组蛋白抑制的 H3K27me3 水平，同时增加了 HDAC 靶向的 H3K27ac 和 LSD1 靶向的 H3K4me1 在分化相关基因上。Corin 处理诱导细胞死亡、细胞周期停滞和细胞分化表型，并导致与 DIPG 患者存活时间增加相关的转录变化。这些数据表明通过同时抑制 LSD1 和 HDACs 来治疗 DIPG 的策略。
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