近日，美国哈佛大学施扬（Yang Shi）和Mariella G. Filbin等研究人员合作发现，用LSD1/HDAC双功能抑制剂能够重编程染色质，从而诱导弥漫性内在脑桥胶质瘤（DIPG）的治疗性分化。 2019年10月17日，国际知名学术期刊《癌细胞》在线发表了这一成果。

研究人员进行了CRISPR筛选，揭示了敲除编码赖氨酸特异性脱甲基酶1（LSD1）的KDM1A基因使DIPG细胞对组蛋白去乙酰化酶（HDAC）抑制剂敏感。Corin是HDAC和LSD1的双功能抑制剂，在体外和异种移植物中均有效抑制DIPG的生长。 从机理上讲，Corin会增加H3K27M组蛋白抑制的H3K27me3水平，并同时增加分化相关基因的HDAC靶向H3K27ac和LSD1靶向H3K4me1。Corin治疗会诱导细胞死亡、细胞周期停滞和细胞分化表型，并驱动与DIPG患者存活时间延长相关的转录变化。这些数据提示了通过同时抑制LSD1和HDAC来治疗DIPG的新策略。

据介绍，H3K27M突变导致表观遗传功能障碍，经常在DIPG（一种无法治愈的小儿癌症）中观察到。

附：英文原文

Title: Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

Author: Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. Filbin, Yang Shi

Issue&Volume: 17 October 2019

Abstract: 

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.

DOI: 10.1016/j.ccell.2019.09.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30425-8