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结直肠癌热点突变减弱了ASXL-MLL4相互作用

Soumi Biswas¹, Ji-Eun Lee², Guojia Xie²

¹Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA.

The Journal of biological chemistry

|February 21, 2025

概括

ASXL-MLL4-BAP1复合体和ASXL突变的变化与结直肠癌 (CRC) 病原发生有关. 这些变化破坏了基因调节,可能导致结肠癌的发展.

科学领域:

分子生物学分子生物学
癌症研究癌症研究
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:

像 (ASXL) 蛋白质这样的额外的性别可以通过与染色质修饰剂相互作用来调节基因表达.
在结直肠癌 (CRC) 中,ASXL基因经常发生变化,ASXL1被确定为关键的枢纽基因.
ASXL蛋白与瘤抑制剂BAP1 (一种二维基提纳酶) 和MLL4 (一种甲基转移酶) 相互作用.

研究的目的:

研究MLL4和BAP1在人类结肠癌细胞内的基因调节中的相互依存作用.
研究ASXL蛋白对MLL4和BAP1在特定基因组区域的向和功能的影响.
确定ASXL基因中CRC相关突变对MLL4-ASXL-BAP1复合体的形成和功能的作用.

主要方法:

染色体免疫沉 (ChIP) 测试以确定MLL4和BAP1的基因组占用率.
同免疫沉试验用于评估蛋白质与蛋白质之间的相互作用.
对ASXL基因的突变分析和结合试验,以评估突变的影响.

主要成果:

MLL4和BAP1在HCT116结肠癌细胞中的基因子集进行同位化并相互依赖地调节.
与胚胎干细胞相比,BAP1在CRC细胞中表现出改变的基因组分布,与增强剂和促进剂的结合增加.
功能性ASXL蛋白对于MLL4+/BAP1+区域的MLL4占用至关重要,与CRC相关的ASXL突变会损害MLL4-ASXL复合体的形成.

结论:

MLL4-ASXL-BAP1轴在维持结肠细胞中正常的转录程序方面发挥着至关重要的作用.
这个轴的基因组分布的变化,加上ASXL突变,可以扰乱基因表达,并导致结肠癌的发病.
准MLL4-ASXL-BAP1复合体可能为结直肠癌提供新的治疗策略.

关键词:

美国证券交易所ASXL1 在 BAP1 中, BAP1 是 BAP1 的第一个类型.在KMT2D中,KMT2D是KMT2D.MLL4LL4 在线阅读在PHD手指指结直肠癌结直肠癌.

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