Advanced Science (Oct 2021)
Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
- 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
Affiliations
- Lihua Wang
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Ergang Wang
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Jorge Prado Balcazar
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Zhenzhen Wu
- Key Laboratory of RNA Biology Key Laboratory of Protein and Peptide Pharmaceutical Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
- Kun Xiang
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Yi Wang
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Qiang Huang
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Marcos Negrete
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Kai‐Yuan Chen
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Wei Li
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Yujie Fu
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Anders Dohlman
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Robert Mines
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Liwen Zhang
- Key Laboratory of RNA Biology Key Laboratory of Protein and Peptide Pharmaceutical Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
- Yoshihiko Kobayashi
- Department of Cell Biology Regeneration Next Duke University School of Medicine Durham NC 27710 USA
- Tianyi Chen
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Guizhi Shi
- Laboratory Animal Research Center Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
- John Paul Shen
- Department of Gastrointestinal Medical Oncology MD Anderson Durham NC 77030 USA
- Scott Kopetz
- Department of Gastrointestinal Medical Oncology MD Anderson Durham NC 77030 USA
- Purushothama Rao Tata
- Department of Cell Biology Regeneration Next Duke University School of Medicine Durham NC 27710 USA
- Victor Moreno
- Department of Clinical Sciences University of Barcelona Barcelona 08193 Spain
- Charles Gersbach
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- Gregory Crawford
- Department of Pediatrics Duke University School of Medicine Durham NC 27710 USA
- David Hsu
- Department of Medicine Duke University School of Medicine Durham NC 27710 USA
- Emina Huang
- Department of Cancer Biology and Colorectal Surgery Lerner Research Institute, Cleveland Clinic Cleveland OH 44195 USA
- Pengcheng Bu
- Key Laboratory of RNA Biology Key Laboratory of Protein and Peptide Pharmaceutical Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China
- Xiling Shen
- Department of Biomedical Engineering Duke University Durham NC 27708 USA
- DOI
- https://doi.org/10.1002/advs.202004673
- Journal volume & issue
-
Vol. 8,
no. 19
pp. n/a – n/a
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.
Keywords
