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

Autor: Wei Li, Anders Dohlman, Jorge Prado Balcazar, Liwen Zhang, Gregory E. Crawford, Kun Xiang, Marcos Negrete, Xiling Shen, Lihua Wang, Purushothama Rao Tata, Zhenzhen Wu, David S. Hsu, Yi Wang, Tianyi Chen, Scott Kopetz, Guizhi Shi, Victor Moreno, Ergang Wang, Emina H. Huang, Charles A. Gersbach, John Paul Shen, Pengcheng Bu, Robert Mines, Qiang Huang, Yoshihiko Kobayashi, Yujie Fu, Kai-Yuan Chen
Rok vydání: 2021
Předmět:
Dipeptidyl Peptidase 4
General Chemical Engineering
hepatic growth factor (HGF)
Science
General Physics and Astronomy
Medicine (miscellaneous)
colorectal cancer
DPP4
Biochemistry
Genetics and Molecular Biology (miscellaneous)
Chromatin remodeling
Epigenesis
Genetic
Metastasis
chromatin remodeling
Mice
Metàstasi
Càncer colorectal
Proto-Oncogene Proteins
medicine
Animals
Humans
Gene silencing
metastasis
General Materials Science
Epigenetics
Promoter Regions
Genetic
Research Articles
Mice
Inbred BALB C
biology
epigenetics
Hepatocyte Growth Factor
Liver Neoplasms
PU.1
Pioneer factor
General Engineering
Cancer
Chromatin Assembly and Disassembly
medicine.disease
Colorectal cancer
Chromatin
Gene Expression Regulation
Neoplastic
Histone
Trans-Activators
biology.protein
Cancer research
Colorectal Neoplasms
Research Article
Zdroj: Dipòsit Digital de la UB
Universidad de Barcelona
Advanced Science, Vol 8, Iss 19, Pp n/a-n/a (2021)
Advanced Science
Popis: 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.
Metastasis of colorectal cancer to the liver is a leading cause of cancer‐related death. This work shows that metastatic colorectal cancer cells undergo chromatin remodeling in the liver via an HGF‐PU.1‐DPP4 axis. Pharmacological or genetic inhibition of this remodeling axis can suppress liver metastasis and prolong survival.
Databáze: OpenAIRE
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