Open AccessChromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
Author(s) -
Wang Lihua,
Wang Ergang,
Prado Balcazar Jorge,
Wu Zhenzhen,
Xiang Kun,
Wang Yi,
Huang Qiang,
Negrete Marcos,
Chen KaiYuan,
Li Wei,
Fu Yujie,
Dohlman Anders,
Mines Robert,
Zhang Liwen,
Kobayashi Yoshihiko,
Chen Tianyi,
Shi Guizhi,
Shen John Paul,
Kopetz Scott,
Tata Purushothama Rao,
Moreno Victor,
Gersbach Charles,
Crawford Gregory,
Hsu David,
Huang Emina,
Bu Pengcheng,
Shen Xiling
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202004673
Subject(s) - chromatin remodeling , metastasis , cancer research , chromatin , gene silencing , histone , epigenetics , biology , colorectal cancer , microbiology and biotechnology , cancer , gene , genetics
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/dCas9 KRAB or CRISPR/dCas9 HDAC 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.