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在HDAC1和HDAC2之间的附带死亡率利用了癌症特异性的NuRD复合体脆弱性

Yuxiang Zhang¹, David Remillard¹, Ugoma Onubogu²

¹Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Nature structural & molecular biology

|July 24, 2023

概括

基脱乙酶1 (HDAC1) 和HDAC2对应物表现出合成杀伤性,提供治疗窗口. 在神经母细胞瘤等缺乏HDAC1的癌症中准HDAC2通过降低NuRD复合体来抑制瘤生长.

科学领域:

癌症生物学癌症生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
分子瘤学分子瘤学

背景情况:

转录协调剂被追求作为癌症药物点,但必需蛋白质限制了治疗选择.
基因脱乙酶1 (HDAC1) 和HDAC2对于基因调节和细胞存活至关重要.
癌症中经常出现的染色体缺失会在重要的基因通路中产生脆弱性.

研究的目的:

为了识别和描述HDAC1和HDAC2对应物之间的合成致命性相互作用.
探索针对这种HDAC1/2合成致死性癌症的治疗潜力.
阐明HDAC1/2合成致死性背后的分子机制及其对癌症依赖性的影响.

主要方法:

基因相互作用分析以确定HDAC1和HDAC2.2之间的合成致死性.
利用基因破坏和dTAG介导的蛋白质降解来准HDAC2.2.
研究HDAC2向对核细胞重塑和脱乙酶 (NuRD) 复合体和染色质可访问性的影响.
分析神经母细胞瘤和多发性骨髓瘤中的癌症依赖性.

主要成果:

HDAC1和HDAC2表现出附带合成杀伤性,其中一个对象的半性删除与另一个对象的删除具有致命性.
在HDAC1-缺乏神经母细胞瘤中准HDAC2抑制了瘤生长在体外和体内.
HDAC2的降解导致NuRD复合体成员的降解,减少染色质可访问性和转录受损.
确定了NuRD复杂子单元作为神经母细胞瘤和多发性髓瘤的依赖性.

结论:

HDAC1/2附带合成致死性为具有特定染色体缺失的癌症提供了一个新的治疗点.
有针对性的HDAC2降解提供了一种利用这种合成致死性和影响NuRD相关癌症依赖性的策略.
开发对等选择性HDAC1或HDAC2降解剂可以利用这种癌症治疗的脆弱性.

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