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CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells

CDKN1C (encoding tumor suppressor p57(KIP2)) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modific...

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Autores principales: Yang, Xiaojing, Karuturi, R. K. Murthy, Sun, Feng, Aau, Meiyee, Yu, Kun, Shao, Rongguang, Miller, Lance D., Tan, Patrick Boon Ooi, Yu, Qiang
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659786/
https://www.ncbi.nlm.nih.gov/pubmed/19340297
http://dx.doi.org/10.1371/journal.pone.0005011
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author Yang, Xiaojing
Karuturi, R. K. Murthy
Sun, Feng
Aau, Meiyee
Yu, Kun
Shao, Rongguang
Miller, Lance D.
Tan, Patrick Boon Ooi
Yu, Qiang
author_facet Yang, Xiaojing
Karuturi, R. K. Murthy
Sun, Feng
Aau, Meiyee
Yu, Kun
Shao, Rongguang
Miller, Lance D.
Tan, Patrick Boon Ooi
Yu, Qiang
author_sort Yang, Xiaojing
collection PubMed
description CDKN1C (encoding tumor suppressor p57(KIP2)) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modifications. In particular, we show that CDKN1C is targeted by histone methyltransferase EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3), and can be strongly activated by inhibition of EZH2 in synergy with histone deacetylase inhibitor. Consistent with the overexpression of EZH2 in a variety of human cancers including breast cancer, CDKN1C in these cancers is downregulated, and breast tumors expressing low levels of CDKN1C are associated with a poor prognosis. We further show that assessing both EZH2 and CDKN1C expression levels as a measurement of EZH2 pathway activity provides a more predictive power of disease outcome than that achieved with EZH2 or CDKN1C alone. Taken together, our study reveals a novel epigenetic mechanism governing CDKN1C repression in breast cancer. Importantly, as a newly identified EZH2 target with prognostic value, it has implications in patient stratification for cancer therapeutic targeting EZH2-mediated gene repression.
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spelling pubmed-26597862009-04-02 CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells Yang, Xiaojing Karuturi, R. K. Murthy Sun, Feng Aau, Meiyee Yu, Kun Shao, Rongguang Miller, Lance D. Tan, Patrick Boon Ooi Yu, Qiang PLoS One Research Article CDKN1C (encoding tumor suppressor p57(KIP2)) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modifications. In particular, we show that CDKN1C is targeted by histone methyltransferase EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3), and can be strongly activated by inhibition of EZH2 in synergy with histone deacetylase inhibitor. Consistent with the overexpression of EZH2 in a variety of human cancers including breast cancer, CDKN1C in these cancers is downregulated, and breast tumors expressing low levels of CDKN1C are associated with a poor prognosis. We further show that assessing both EZH2 and CDKN1C expression levels as a measurement of EZH2 pathway activity provides a more predictive power of disease outcome than that achieved with EZH2 or CDKN1C alone. Taken together, our study reveals a novel epigenetic mechanism governing CDKN1C repression in breast cancer. Importantly, as a newly identified EZH2 target with prognostic value, it has implications in patient stratification for cancer therapeutic targeting EZH2-mediated gene repression. Public Library of Science 2009-04-02 /pmc/articles/PMC2659786/ /pubmed/19340297 http://dx.doi.org/10.1371/journal.pone.0005011 Text en Yang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yang, Xiaojing
Karuturi, R. K. Murthy
Sun, Feng
Aau, Meiyee
Yu, Kun
Shao, Rongguang
Miller, Lance D.
Tan, Patrick Boon Ooi
Yu, Qiang
CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title_full CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title_fullStr CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title_full_unstemmed CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title_short CDKN1C (p57(KIP2)) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
title_sort cdkn1c (p57(kip2)) is a direct target of ezh2 and suppressed by multiple epigenetic mechanisms in breast cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659786/
https://www.ncbi.nlm.nih.gov/pubmed/19340297
http://dx.doi.org/10.1371/journal.pone.0005011
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