Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.
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.
Wang, L; Wang, E; Prado Balcazar, J; Wu, Z; Xiang, K; Wang, Y; Huang, Q; Negrete, M; Chen, K-Y; Li, W; Fu, Y; Dohlman, A; Mines, R; Zhang, L; Kobayashi, Y; Chen, T; Shi, G; Shen, JP; Kopetz, S; Tata, PR; Moreno, V; Gersbach, C; Crawford, G; Hsu, D; Huang, E; Bu, P; Shen, X
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