Cargando…

The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells

Cancer cells exhibit phenotypic plasticity during epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) involving intermediate states. To study genome-wide epigenetic remodeling associated with EMT plasticity, we integrate the analyses of DNA methylation, ChIP-sequencin...

Descripción completa

Detalles Bibliográficos
Autores principales: Chung, Vin Yee, Tan, Tuan Zea, Ye, Jieru, Huang, Rui-Lan, Lai, Hung-Cheng, Kappei, Dennis, Wollmann, Heike, Guccione, Ernesto, Huang, Ruby Yun-Ju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656769/
https://www.ncbi.nlm.nih.gov/pubmed/31372511
http://dx.doi.org/10.1038/s42003-019-0506-3
_version_ 1783438683448279040
author Chung, Vin Yee
Tan, Tuan Zea
Ye, Jieru
Huang, Rui-Lan
Lai, Hung-Cheng
Kappei, Dennis
Wollmann, Heike
Guccione, Ernesto
Huang, Ruby Yun-Ju
author_facet Chung, Vin Yee
Tan, Tuan Zea
Ye, Jieru
Huang, Rui-Lan
Lai, Hung-Cheng
Kappei, Dennis
Wollmann, Heike
Guccione, Ernesto
Huang, Ruby Yun-Ju
author_sort Chung, Vin Yee
collection PubMed
description Cancer cells exhibit phenotypic plasticity during epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) involving intermediate states. To study genome-wide epigenetic remodeling associated with EMT plasticity, we integrate the analyses of DNA methylation, ChIP-sequencing of five histone marks (H3K4me1, H3K4me3, H3K27Ac, H3K27me3 and H3K9me3) and transcriptome profiling performed on ovarian cancer cells with different epithelial/mesenchymal states and on a knockdown model of EMT suppressor Grainyhead-like 2 (GRHL2). We have identified differentially methylated CpG sites associated with EMT, found at promoters of epithelial genes and GRHL2 binding sites. GRHL2 knockdown results in CpG methylation gain and nucleosomal remodeling (reduction in permissive marks H3K4me3 and H3K27ac; elevated repressive mark H3K27me3), resembling the changes observed across progressive EMT states. Epigenetic-modifying agents such as 5-azacitidine, GSK126 and mocetinostat further reveal cell state-dependent plasticity upon GRHL2 overexpression. Overall, we demonstrate that epithelial genes are subject to epigenetic control during intermediate phases of EMT/MET involving GRHL2.
format Online
Article
Text
id pubmed-6656769
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-66567692019-08-01 The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells Chung, Vin Yee Tan, Tuan Zea Ye, Jieru Huang, Rui-Lan Lai, Hung-Cheng Kappei, Dennis Wollmann, Heike Guccione, Ernesto Huang, Ruby Yun-Ju Commun Biol Article Cancer cells exhibit phenotypic plasticity during epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) involving intermediate states. To study genome-wide epigenetic remodeling associated with EMT plasticity, we integrate the analyses of DNA methylation, ChIP-sequencing of five histone marks (H3K4me1, H3K4me3, H3K27Ac, H3K27me3 and H3K9me3) and transcriptome profiling performed on ovarian cancer cells with different epithelial/mesenchymal states and on a knockdown model of EMT suppressor Grainyhead-like 2 (GRHL2). We have identified differentially methylated CpG sites associated with EMT, found at promoters of epithelial genes and GRHL2 binding sites. GRHL2 knockdown results in CpG methylation gain and nucleosomal remodeling (reduction in permissive marks H3K4me3 and H3K27ac; elevated repressive mark H3K27me3), resembling the changes observed across progressive EMT states. Epigenetic-modifying agents such as 5-azacitidine, GSK126 and mocetinostat further reveal cell state-dependent plasticity upon GRHL2 overexpression. Overall, we demonstrate that epithelial genes are subject to epigenetic control during intermediate phases of EMT/MET involving GRHL2. Nature Publishing Group UK 2019-07-24 /pmc/articles/PMC6656769/ /pubmed/31372511 http://dx.doi.org/10.1038/s42003-019-0506-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chung, Vin Yee
Tan, Tuan Zea
Ye, Jieru
Huang, Rui-Lan
Lai, Hung-Cheng
Kappei, Dennis
Wollmann, Heike
Guccione, Ernesto
Huang, Ruby Yun-Ju
The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title_full The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title_fullStr The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title_full_unstemmed The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title_short The role of GRHL2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
title_sort role of grhl2 and epigenetic remodeling in epithelial–mesenchymal plasticity in ovarian cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656769/
https://www.ncbi.nlm.nih.gov/pubmed/31372511
http://dx.doi.org/10.1038/s42003-019-0506-3
work_keys_str_mv AT chungvinyee theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT tantuanzea theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT yejieru theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT huangruilan theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT laihungcheng theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT kappeidennis theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT wollmannheike theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT guccioneernesto theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT huangrubyyunju theroleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT chungvinyee roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT tantuanzea roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT yejieru roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT huangruilan roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT laihungcheng roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT kappeidennis roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT wollmannheike roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT guccioneernesto roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells
AT huangrubyyunju roleofgrhl2andepigeneticremodelinginepithelialmesenchymalplasticityinovariancancercells