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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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Autores principales: 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, Victor, Gersbach, Charles, Crawford, Gregory, Hsu, David, Huang, Emina, Bu, Pengcheng, Shen, Xiling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498885/
https://www.ncbi.nlm.nih.gov/pubmed/34378358
http://dx.doi.org/10.1002/advs.202004673
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author 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, Victor
Gersbach, Charles
Crawford, Gregory
Hsu, David
Huang, Emina
Bu, Pengcheng
Shen, Xiling
author_facet 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, Victor
Gersbach, Charles
Crawford, Gregory
Hsu, David
Huang, Emina
Bu, Pengcheng
Shen, Xiling
author_sort Wang, Lihua
collection PubMed
description 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/dCas9(KRAB) or CRISPR/dCas9(HDAC) 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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spelling pubmed-84988852021-10-12 Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis 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, Victor Gersbach, Charles Crawford, Gregory Hsu, David Huang, Emina Bu, Pengcheng Shen, Xiling Adv Sci (Weinh) Research Articles 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/dCas9(KRAB) or CRISPR/dCas9(HDAC) 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. John Wiley and Sons Inc. 2021-08-10 /pmc/articles/PMC8498885/ /pubmed/34378358 http://dx.doi.org/10.1002/advs.202004673 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
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, Victor
Gersbach, Charles
Crawford, Gregory
Hsu, David
Huang, Emina
Bu, Pengcheng
Shen, Xiling
Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title_full Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title_fullStr Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title_full_unstemmed Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title_short Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF‐PU.1‐DPP4 Axis
title_sort chromatin remodeling of colorectal cancer liver metastasis is mediated by an hgf‐pu.1‐dpp4 axis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498885/
https://www.ncbi.nlm.nih.gov/pubmed/34378358
http://dx.doi.org/10.1002/advs.202004673
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