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Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis

Authors :
Lihua Wang
Ergang Wang
Jorge Prado Balcazar
Zhenzhen Wu
Kun Xiang
Yi Wang
Qiang Huang
Marcos Negrete
Kai‐Yuan Chen
Wei Li
Yujie Fu
Anders Dohlman
Robert Mines
Liwen Zhang
Yoshihiko Kobayashi
Tianyi Chen
Guizhi Shi
John Paul Shen
Scott Kopetz
Purushothama Rao Tata
Victor Moreno
Charles Gersbach
Gregory Crawford
David Hsu
Emina Huang
Pengcheng Bu
Xiling Shen
Source :
Advanced Science, Vol 8, Iss 19, Pp n/a-n/a (2021)
Publication Year :
2021
Publisher :
Wiley, 2021.

Abstract

Abstract Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC‐related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1‐remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment‐induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.

Details

Language :
English
ISSN :
21983844
Volume :
8
Issue :
19
Database :
Directory of Open Access Journals
Journal :
Advanced Science
Publication Type :
Academic Journal
Accession number :
edsdoj.9e4ca4741b44963bbd7506d05a7e116
Document Type :
article
Full Text :
https://doi.org/10.1002/advs.202004673