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Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer
Nature Biomedical Engineering ( IF 28.1 ) Pub Date : 2020-12-07 , DOI: 10.1038/s41551-020-00657-x
Minjeong Jang 1 , Jinhyeon An 1 , Seung Won Oh 1 , Joo Yeon Lim 2 , Joon Kim 3 , Jung Kyoon Choi 1 , Jae-Ho Cheong 2 , Pilnam Kim 1, 4
Affiliation  

In many cancers, tumour progression is associated with increased tissue stiffness. Yet, the mechanisms associating tissue stiffness with tumorigenesis and malignant transformation are unclear. Here we show that in gastric cancer cells, the stiffness of the extracellular matrix reversibly regulates the DNA methylation of the promoter region of the mechanosensitive Yes-associated protein (YAP). Reciprocal interactions between YAP and the DNA methylation inhibitors GRHL2, TET2 and KMT2A can cause hypomethylation of the YAP promoter and stiffness-induced oncogenic activation of YAP. Direct alteration of extracellular cues via in situ matrix softening reversed YAP activity and the epigenetic program. Our findings suggest that epigenetic reprogramming of the mechanophysical properties of the extracellular microenvironment of solid tumours may represent a therapeutic strategy for the inhibition of cancer progression.



中文翻译:

基质硬度表观遗传调节胃癌中 Yes 相关蛋白的致癌激活

在许多癌症中,肿瘤进展与组织硬度增加有关。然而,将组织硬度与肿瘤发生和恶性转化相关联的机制尚不清楚。在这里,我们表明在胃癌细胞中,细胞外基质的硬度可逆地调节机械敏感 Yes 相关蛋白 (YAP) 启动子区域的 DNA 甲基化。YAP 与 DNA 甲基化抑制剂 GRHL2、TET2 和 KMT2A 之间的相互作用可导致 YAP 启动子的低甲基化和 YAP 的僵硬诱导致癌激活。通过原位基质软化直接改变细胞外信号可逆转 YAP 活性和表观遗传程序。

更新日期:2020-12-07
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