Matrix stiffness epigenetically regulates the oncogenic activation of the Yes-associated protein in gastric cancer.

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.