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

Thumbnail Image
View / Download5.31 MB

Date

2021-10

Authors

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

5
views
13
downloads

Citation Stats

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.

Type

Journal article

Department

Description

Provenance

Subjects

Animals, Mice, Inbred BALB C, Humans, Mice, Colorectal Neoplasms, Liver Neoplasms, Hepatocyte Growth Factor, Trans-Activators, Proto-Oncogene Proteins, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Promoter Regions, Genetic, Dipeptidyl Peptidase 4

Citation

Permalink

https://hdl.handle.net/10161/29046

Published Version (Please cite this version)

10.1002/advs.202004673

Publication Info

Wang, Lihua, Ergang Wang, Jorge Prado Balcazar, Zhenzhen Wu, Kun Xiang, Yi Wang, Qiang Huang, Marcos Negrete, et al. (2021). Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8(19). p. e2004673. 10.1002/advs.202004673 Retrieved from https://hdl.handle.net/10161/29046.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Collections

Scholarly Articles
Full item page

Scholars@Duke

Tata

Purushothama Rao Tata

Associate Professor of Cell Biology

Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology

Gersbach

Charles Gersbach

John W. Strohbehn Distinguished Professor of Biomedical Engineering
Crawford

Gregory E. Crawford

Professor in Pediatrics

My primary research interest is understanding how the genome is regulated.  The human genome contains approximately 25,000 genes, which are encoded in ~2% of the genome. The overarching goal of my research program is to identify and characterize how these genes are turned on and off in different cell types, tissues, development states, environmental responses, diseases, and individuals. By understanding where all gene regulatory elements are located, how they work to regulate gene expression, and how non-coding variants within these regions affect function, my research program can address a number of important basic and clinical questions.

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.