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FBXO44促进癌细胞中的DNA复制合重复元件沉默

Jia Z Shen¹, Zhixin Qiu², Qiulian Wu²

¹Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

|December 28, 2020

概括

FBXO44和SUV39H1通常会抑制基因组中的重复元素. 在癌细胞中抑制它们会重新激活这些元素,导致复制压力和增强抗瘤免疫力.

科学领域:

基因组学
表观遗传学
癌症生物学

背景情况:

人类基因组中的重复元素约占50%.
控制RE转录沉默的精确机制在很大程度上是未知的.
在各种病态中,包括癌症中,都涉及到RE的失调.

研究的目的:

确定重复元素 (RE) 转录的新型调节剂.
阐明FBXO44在RE沉默中的作用及其对癌症的影响.
研究针对RE抑制途径的治疗潜力.

主要方法:

通过RNA干扰 (RNAi) 查来识别RE抑制剂.
染色体免疫沉 (ChIP) 试验用于研究蛋白质核酶相互作用.
对DNA复制压力标志物和抗病毒信号通路 (MAVS/STING) 的分析.
在人类癌症中,FBXO44表达和免疫细胞透之间的相关性研究.

主要成果:

FBXO44被确定为癌细胞中RE的关键抑制剂.
FBXO44使用SUV39H1,CRL4和Mi-2/NuRD来沉默复制后的RE.
抑制FBXO44/ SUV39H1重新激活的RE,诱导的复制应激,以及激活的MAVS/ STING/ 干扰素通路.
抑制FBXO44/SUV39H1可以选择性地影响癌细胞,而不会影响正常细胞.
FBXO44表达与免疫标志物相反相关,与患者免疫治疗反应相对正相关.

结论:

在癌症中,FBXO44和SUV39H1对于保持转录性沉默至关重要.
向FBXO44/SUV39H1可以选择性地诱导癌细胞中的DNA复制压力和病毒模拟.
这种策略增强了癌症的免疫性,并改善了对免疫治疗的反应.

关键词:

在FBXO44 H3K9me3 其他在SUV39H1 免疫疗法重复的元素

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