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

Oncogene volume 27, pages 7274–7284 (2008)Cite this article

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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Acknowledgements

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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Author notes

  1. S Varambally and A M Chinnaiyan: SV and AMC share senior authorship.

Authors and Affiliations

  1. Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    Q Cao, J Yu, S M Dhanasekaran, J H Kim, R-S Mani, S A Tomlins, R Mehra, B Laxman, X Cao, J Yu, S Varambally & A M Chinnaiyan

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

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

  3. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA

    R Mehra, C G Kleer, S Varambally & A M Chinnaiyan

  4. Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA

    X Cao & A M Chinnaiyan

  5. Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA

    A M Chinnaiyan

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  1. Q Cao
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Correspondence to A M Chinnaiyan.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Cao, Q., Yu, J., Dhanasekaran, S. et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27, 7274–7284 (2008). https://doi.org/10.1038/onc.2008.333

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