Repression of E-cadherin by the polycomb group protein EZH2 in cancer

Q. Cao; J. Yu; S. M. Dhanasekaran; J. H. Kim; R. S. Mani; S. A. Tomlins; R. Mehra; B. Laxman; X. Cao; J. Yu; C. G. Kleer; S. Varambally; A. M. Chinnaiyan

doi:10.1038/onc.2008.333

Repression of E-cadherin by the polycomb group protein EZH2 in cancer

Q. Cao, J. Yu, S. M. Dhanasekaran, J. H. Kim, R. S. Mani, S. A. Tomlins, R. Mehra, B. Laxman, X. Cao, J. Yu, C. G. Kleer, S. Varambally, A. M. Chinnaiyan

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

520 Scopus citations

Abstract

Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.

Original language	English (US)
Pages (from-to)	7274-7284
Number of pages	11
Journal	Oncogene
Volume	27
Issue number	58
DOIs	https://doi.org/10.1038/onc.2008.333
State	Published - Dec 11 2008

Funding

We thank Professor Eric Fearon for providing the E-cadherin promoter–reporter constructs. We thank Jill Granger for critically reading the paper and for her thoughtful suggestions. We thank R Kunkel for help in figure preparation and the staff of the Microscopy and Image Analyses laboratory at the University of Michigan for their assistance in the microscopic analyses employed in this study. We thank the University of Michigan Vector Core for virus generation. AMC is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research. SAT is supported by the Medical Scientist Training Program and a Rackham Pre-doctoral Award. This research was supported in part by National Institutes of Health Grant RO1 CA97063 (to AMC); U01 CA111275 (to AMC); P50 CA69568 (to AMC); Department of Defense Grants PC040517 (to RM), PC051081 (to AMC and SV), PC060266 (to JY) and R01CA107469 (to CGK).

Keywords

E-cadherin
EZH2
Epigenetics
Histone
Polycomb group protein

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/onc.2008.333

Cite this

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title = "Repression of E-cadherin by the polycomb group protein EZH2 in cancer",

abstract = "Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.",

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author = "Q. Cao and J. Yu and Dhanasekaran, \{S. M.\} and Kim, \{J. H.\} and Mani, \{R. S.\} and Tomlins, \{S. A.\} and R. Mehra and B. Laxman and X. Cao and J. Yu and Kleer, \{C. G.\} and S. Varambally and Chinnaiyan, \{A. M.\}",

note = "Funding Information: We thank Professor Eric Fearon for providing the E-cadherin promoter–reporter constructs. We thank Jill Granger for critically reading the paper and for her thoughtful suggestions. We thank R Kunkel for help in figure preparation and the staff of the Microscopy and Image Analyses laboratory at the University of Michigan for their assistance in the microscopic analyses employed in this study. We thank the University of Michigan Vector Core for virus generation. AMC is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research. SAT is supported by the Medical Scientist Training Program and a Rackham Pre-doctoral Award. This research was supported in part by National Institutes of Health Grant RO1 CA97063 (to AMC); U01 CA111275 (to AMC); P50 CA69568 (to AMC); Department of Defense Grants PC040517 (to RM), PC051081 (to AMC and SV), PC060266 (to JY) and R01CA107469 (to CGK).",

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doi = "10.1038/onc.2008.333",

language = "English (US)",

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AU - Cao, Q.

AU - Yu, J.

AU - Dhanasekaran, S. M.

AU - Kim, J. H.

AU - Mani, R. S.

AU - Tomlins, S. A.

AU - Mehra, R.

AU - Laxman, B.

AU - Cao, X.

AU - Yu, J.

AU - Kleer, C. G.

AU - Varambally, S.

AU - Chinnaiyan, A. M.

N1 - Funding Information: We thank Professor Eric Fearon for providing the E-cadherin promoter–reporter constructs. We thank Jill Granger for critically reading the paper and for her thoughtful suggestions. We thank R Kunkel for help in figure preparation and the staff of the Microscopy and Image Analyses laboratory at the University of Michigan for their assistance in the microscopic analyses employed in this study. We thank the University of Michigan Vector Core for virus generation. AMC is supported by a Burroughs Welcome Foundation Award in Clinical Translational Research. SAT is supported by the Medical Scientist Training Program and a Rackham Pre-doctoral Award. This research was supported in part by National Institutes of Health Grant RO1 CA97063 (to AMC); U01 CA111275 (to AMC); P50 CA69568 (to AMC); Department of Defense Grants PC040517 (to RM), PC051081 (to AMC and SV), PC060266 (to JY) and R01CA107469 (to CGK).

PY - 2008/12/11

Y1 - 2008/12/11

N2 - Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.

AB - Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.

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KW - Epigenetics

KW - Histone

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JF - Oncogene

IS - 58

ER -

Repression of E-cadherin by the polycomb group protein EZH2 in cancer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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