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增加的NSD3基因组甲基化活性导致状细胞肺癌

Gang Yuan¹, Natasha M Flores², Simone Hausmann²

¹Department of Biology, Stanford University, Stanford, CA, USA.

|February 4, 2021

概括

基因组甲基转移酶NSD3是由8p11-12安普利康驱动的肺状细胞癌 (LUSC) 的关键驱动因素. 向NSD3,而不是FGFR1,在LUSC中显示出治疗潜力,特别是在代体抑制剂中.

科学领域:

癌症学
遗传学
表观遗传学

背景情况:

在肺状细胞癌 (LUSC) 中,8p11-12染色体区域的放大很常见.
FGFR1被认为是主要的驱动因素,但在临床试验中,FGFR1抑制失败了.
作为一个潜在的驱动因素,NSD3是位于8p11-12amplicon中的 histone H3 lysine 36甲基转移酶.

研究的目的:

在LUSC的8p11-12 amplicon中识别瘤发生的关键驱动因素.
研究NSD3在LUSC发展中的作用及其治疗影响.
探索NSD3依赖的LUSC的治疗脆弱性.

主要方法:

在LUSC中对NSD3表达和基因放大的相关性分析.
在体外和体内研究涉及NSD3剥离和LUSC模型中的变异表达.
对NSD3催化活性进行结构动态分析.
评估NSD3在人类细胞转化和异种移植生长中的作用.
在NSD3调节的LUSC异种移植中评估代蛋白抑制.

主要成果:

与FGFR1不同的是,NSD3表达与LUSC中的基因放大有很强的相关性.
在小鼠模型中,NSD3的切除,而不是FGFR1的切除,降低了瘤生长和改善了生存率.
一种与LUSC相关的变体NSD3 (T1232A) 呈现出增强的催化活性,加速瘤形成并降低存活率.
NSD3 ((T1232A) 重新编程染色体,促进致癌基因表达.
在患者衍生的异种移植中,NSD3 枯竭减弱了瘤生长,而NSD3 调节的异种移植对主体抑制敏感.

结论:

NSD3被确定为与8p11-12片相关的LUSC的主要致癌驱动因素.
NSD3的催化活性及其变体NSD3 (T1232A) 对LUSC瘤发生至关重要.
由于对NSD3的依赖,LUSC在治疗上容易受到主体抑制的影响.

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