Advanced Science, 10 August, 2021, DOI：https://doi.org/10.1002/advs.202004673
Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis
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
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.