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EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor

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Abstract

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase polycomb group (PcG) protein, which has been implicated in the process of cellular differentiation and cancer progression for both breast and prostate cancer. Although transcriptional repression by histone modification appears to contribute to the process of cellular differentiation, it is unclear what mediates the specificity of PcG proteins. Since EZH2 requires a binding partner for its histone methyltransferase activity, we surmised that evaluating interacting proteins might shed light on how the activity of EZH2 is regulated. Here we describe the identification of a novel binding partner of EZH2, the repressor of estrogen receptor activity (REA). REA functions as a transcriptional corepressor of the estrogen receptor and can potentiate the effect of anti-estrogens. REA expression levels have also previously been associated with the degree of differentiation of human breast cancers. We show here that EZH2 can also mediate the repression of estrogen-dependent transcription, and that moreover, the ability of both REA and EZH2 to repress estrogen-dependent transcription are mutually dependent. These data suggest that EZH2 may be recruited to specific target genes by its interaction with the estrogen receptor corepressor REA. The identification of a novel interaction between EZH2 and REA, two transcription factors that have been linked to breast cancer carcinogenesis, may lead to further insights into the process of deregulated gene expression in breast cancer.

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Acknowledgments

We thank Dr. Ron Koenig of the University of Michigan for his kind gift of the ER-expressing and ERE-luciferase reporter plasmids. We also acknowledge members of the Duckett lab for helpful discussions and critical reading of this manuscript. In addition, we specifically thank Karolyn Oetjen and David Kosoff for their contributions to this work. This work was supported by a grant from the Department of Defense (W81XWH-04-1-0314).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109-0602, USA

    Clara Hwang, Kathleen A. Cooney & Colin S. Duckett

  2. Population Sciences and Medical Oncology, Fox Chase Cancer Center, Cheltenham, PA, 19012, USA

    Veda N. Giri

  3. Department of Pathology, University of Michigan Medical School, Room 2000, 109 Zina Pitcher Pl, Ann Arbor, MI, 48109, USA

    John C. Wilkinson, Casey W. Wright, Amanda S. Wilkinson & Colin S. Duckett

  4. Department of Urology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Kathleen A. Cooney

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  1. Clara Hwang
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  2. Veda N. Giri
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  3. John C. Wilkinson
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  4. Casey W. Wright
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  5. Amanda S. Wilkinson
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  7. Colin S. Duckett
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Correspondence to Colin S. Duckett.

Additional information

Clara Hwang and Veda N. Giri contributed equally to this work.

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Hwang, C., Giri, V.N., Wilkinson, J.C. et al. EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor. Breast Cancer Res Treat 107, 235–242 (2008). https://doi.org/10.1007/s10549-007-9542-7

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  • DOI: https://doi.org/10.1007/s10549-007-9542-7

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