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Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

Oncogene volume 23, pages 4930–4937 (2004)Cite this article

Abstract

The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130–HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation.

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Acknowledgements

We thank Dr A Otte for the monoclonal anti-Ezh2 antibody and Dr A Ullrich for the polyclonal anti-Ezh2. We are grateful to Dr AM Chinnaiyan who kindly provided the myc-tagged Ezh2 and Dr GP Tuszynski for providing Hs 578Bst, Hs 578T and NPTX-1532 cell lines. We thank Dr K Reiss for his critical suggestions. We are grateful to Dr C Gabellini for her expertise in editing the figures, and Ms M Basso for her assistance in editing the manuscript. This work was supported by Sbarro Health Research Organization and NIH grants (AG and by the WW Shith Charitable Trust (PPC)). TT was supported by “Dottorato in Patologia Diagnostica e Quantitativa”, University of Siena, Italy.

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Authors and Affiliations

  1. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, 19122, PA, USA

    Tiziana Tonini, Luigi Bagella, Giuseppina D'Andrilli, Pier Paolo Claudio & Antonio Giordano

  2. Department of Human Pathology and Oncology, University of Siena Nuovo Policlinico “Le Scotte” Via delle Scotte, 6,53100, Siena, Italy

    Tiziana Tonini, Luigi Bagella & Antonio Giordano

  3. Department of “Scienze Odontostomatologiche e Maxillo Facciali”, Naples, Italy

    Pier Paolo Claudio

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  1. Tiziana Tonini
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Correspondence to Antonio Giordano.

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Tonini, T., Bagella, L., D'Andrilli, G. et al. Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A. Oncogene 23, 4930–4937 (2004). https://doi.org/10.1038/sj.onc.1207608

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