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氨酸甲基化促进NFAT5的激活,并决定了temozolomide在质母细胞瘤中的疗效

Yatian Li¹, Zhenyue Gao², Yuhong Wang¹

¹Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Nature communications

|July 10, 2023

概括

泰莫佐洛米德 (TMZ) 对高EGFR活性质母细胞瘤具有有限的益处. 向NFAT5甲基化,这是TMZ耐药性的关键因素,是一个有前途的组合疗法策略,以提高治疗疗效.

科学领域:

分子瘤学分子瘤学
癌症治疗方法癌症治疗方法
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

在高表皮生长因子受体 (EGFR) 活性的多形质母细胞瘤 (GBM) 中,Temozolomide (TMZ) 的疗效有限.
需要新的治疗策略来克服TMZ在GBM中的耐药性.
强度响应增强剂结合蛋白 (NFAT5) 在TMZ反应中的作用尚未被探索.

研究的目的:

研究NFAT5氨酸甲基化的作用,作为在GBM中TMZ反应的决定因素.
阐明将EGFR激活,NFAT5甲基化和TMZ耐药性联系在一起的分子机制.
在临床前的GBM模型中评估抑制NFAT5甲基化的治疗潜力.

主要方法:

研究了EGFR介导的信号通路,导致NFAT5甲基化.
利用细胞系和患者衍生异种移植 (PDX) 来评估NFAT5甲基化对TMZ疗效的影响.
在TMZ耐火性GBM标本中分析了NFAT5 K668甲基化水平.

主要成果:

EGFR激活会在K668处诱导EZH2介导的NFAT5甲基化,稳定蛋白质并促进核积累.
甲基化NFAT5可以提高MGMT的调节,MGMT是TMZ耐药性的关键媒介.
在临床前的GBM模型中,抑制NFAT5 K668甲基化显著提高了TMZ的疗效.
较高的NFAT5 K668甲基化水平与TMZ折射性和患者的预后不佳相关.

结论:

NFAT5 K668甲基化是推动EGFR激活的GBM中TMZ耐药性的关键机制.
向NFAT5甲基化是一种有希望的治疗策略,可以增强TMZ反应.
这种方法有可能改善EGFR驱动性质母细胞瘤患者的治疗结果.

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