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

doi:10.1002/advs.202004673

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 TataVictor Moreno, Charles Gersbach, Gregory Crawford, David Hsu, Emina Huang, Pengcheng Bu, Xiling Shen

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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/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.

Original language	English (US)
Article number	2004673
Journal	Advanced Science
Volume	8
Issue number	19
DOIs	https://doi.org/10.1002/advs.202004673
State	Published - Oct 6 2021
Externally published	Yes

Keywords

DPP4
PU.1
chromatin remodeling
colorectal cancer
epigenetics
hepatic growth factor (HGF)
metastasis

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
General Materials Science
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Engineering
General Physics and Astronomy

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10.1002/advs.202004673

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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, J. P., Kopetz, S., ... Shen, X. (2021). Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis. Advanced Science, 8(19), Article 2004673. https://doi.org/10.1002/advs.202004673

Wang, L, Wang, E, Prado Balcazar, J, Wu, Z, Xiang, K, Wang, Y, Huang, Q, Negrete, M, Chen, KY, 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 2021, 'Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis', Advanced Science, vol. 8, no. 19, 2004673. https://doi.org/10.1002/advs.202004673

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title = "Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis",

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 = "DPP4, PU.1, chromatin remodeling, colorectal cancer, epigenetics, hepatic growth factor (HGF), metastasis",

author = "Lihua Wang and Ergang Wang and {Prado Balcazar}, Jorge and Zhenzhen Wu and Kun Xiang and Yi Wang and Qiang Huang and Marcos Negrete and Chen, {Kai Yuan} and Wei Li and Yujie Fu and Anders Dohlman and Robert Mines and Liwen Zhang and Yoshihiko Kobayashi and Tianyi Chen and Guizhi Shi and Shen, {John Paul} and Scott Kopetz and Tata, {Purushothama Rao} and Victor Moreno and Charles Gersbach and Gregory Crawford and David Hsu and Emina Huang and Pengcheng Bu and Xiling Shen",

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AU - Wang, Lihua

AU - Wang, Ergang

AU - Prado Balcazar, Jorge

AU - Wu, Zhenzhen

AU - Xiang, Kun

AU - Wang, Yi

AU - Huang, Qiang

AU - Negrete, Marcos

AU - Chen, Kai Yuan

AU - Li, Wei

AU - Fu, Yujie

AU - Dohlman, Anders

AU - Mines, Robert

AU - Zhang, Liwen

AU - Kobayashi, Yoshihiko

AU - Chen, Tianyi

AU - Shi, Guizhi

AU - Shen, John Paul

AU - Kopetz, Scott

AU - Tata, Purushothama Rao

AU - Moreno, Victor

AU - Gersbach, Charles

AU - Crawford, Gregory

AU - Hsu, David

AU - Huang, Emina

AU - Bu, Pengcheng

AU - Shen, Xiling

PY - 2021/10/6

Y1 - 2021/10/6

N2 - 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.

AB - 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.

KW - DPP4

KW - PU.1

KW - chromatin remodeling

KW - colorectal cancer

KW - epigenetics

KW - hepatic growth factor (HGF)

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Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis

Abstract

Keywords

ASJC Scopus subject areas

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