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 bin...

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Detalles Bibliográficos
Autores: Wang, Lihua, Wang, Ergang, Prado Balcazar, Jorge, Wu, Zhenzhen, Xiang, Kun, Wang, Yi, Huang, Qiang, Negrete, Marcos, Chen, Kai‐yuan, Li, Wei, Fu, Yujie, Dohlman, Anders, Mines, Robert, Zhang, Liwen, Kobayashi, Yoshihiko, Chen, Tianyi, Shi, Guizhi, Shen, John Paul, Kopetz, Scott, Tata, Purushothama Rao, Moreno Aguado, Víctor, Gersbach, Charles, Crawford, Gregory, Hsu, David, Huang, Emina, Bu, Pengcheng, Shen, Xiling
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/179937
Acceso en línea:https://hdl.handle.net/2445/179937
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Metàstasi
Colorectal cancer
Metastasis
Descripción
Sumario: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.

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