细胞外基质
表观遗传学
DNA甲基化
重编程
癌变
癌症研究
癌症
生物
甲基化
机械敏感通道
恶性转化
细胞生物学
化学
DNA
遗传学
基因表达
基因
受体
离子通道
作者
Mi Jin Jang,Jinhyeon An,Seung Won Oh,Joo Yeon Lim,Joon Kim,Jung Kyoon Choi,Jae‐Ho Cheong,Pilnam Kim
标识
DOI:10.1038/s41551-020-00657-x
摘要
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.
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