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

Authors
 Minjeong Jang  ;  Jinhyeon An  ;  Seung Won Oh  ;  Joo Yeon Lim  ;  Joon Kim  ;  Jung Kyoon Choi  ;  Jae-Ho Cheong  ;  Pilnam Kim 
Citation
 NATURE BIOMEDICAL ENGINEERING, Vol.5(1) : 114-123, 2021-01 
Journal Title
NATURE BIOMEDICAL ENGINEERING
Issue Date
2021-01
MeSH
Adaptor Proteins, Signal Transducing* / genetics ; Adaptor Proteins, Signal Transducing* / metabolism ; Carcinogenesis* / genetics ; Carcinogenesis* / metabolism ; Cell Line, Tumor ; DNA Methylation* / genetics ; DNA Methylation* / physiology ; Epigenesis, Genetic / genetics ; Epigenesis, Genetic / physiology ; Extracellular Matrix* / chemistry ; Extracellular Matrix* / genetics ; Extracellular Matrix* / metabolism ; Humans ; Mechanotransduction, Cellular / genetics ; Mechanotransduction, Cellular / physiology ; Stomach Neoplasms* / genetics ; Stomach Neoplasms* / metabolism ; Stomach Neoplasms* / physiopathology ; Transcription Factors* / genetics ; Transcription Factors* / metabolism ; Tumor Microenvironment / genetics ; Tumor Microenvironment / physiology
Abstract
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.
Full Text
https://www.nature.com/articles/s41551-020-00657-x
DOI
10.1038/s41551-020-00657-x
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/181961
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