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EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer

The EMBO Journal volume 22, pages 5323–5335 (2003)Cite this article

Abstract

Recent experiments have demonstrated that the Polycomb group (PcG) gene EZH2 is highly expressed in metastatic prostate cancer and in lymphomas. EZH2 is a component of the PRC2 histone methyltransferase complex, which also contains EED and SUZ12 and is required for the silencing of HOX gene expression during embryonic development. Here we demonstrate that both EZH2 and EED are essential for the proliferation of both transformed and non‐transformed human cells. In addition, the pRB‐E2F pathway tightly regulates their expression and, consistent with this, we find that EZH2 is highly expressed in a large set of human tumors. These results raise the question whether EZH2 is a marker of proliferation or if it is actually contributing to tumor formation. Significantly, we propose that EZH2 is a bona fide oncogene, since we find that ectopic expression of EZH2 is capable of providing a proliferative advantage to primary cells and, in addition, its gene locus is specifically amplified in several primary tumors.

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Acknowledgements

We thank Daniele Piccini for the generation of anti‐EED antibody, Emma Hickman for help in performing MEF assays, Emmanuela Frittoli for help with microinjection experiments, Manuela Nebuloni and Renzo Boldorini for providing tumor material, Micaela Quarto and Marco Bianchi for generation of TMAs and for ISH analysis, Eros Lazzerini‐Denchi for his expertise in mouse myoblast differentiation and critical reading of the manuscript and Patrizia Gasparini for technical advice regarding FISH analysis. We thank Bruno Amati, Jiri Bartek, Thomas Jenuwein, Arie Otte and Liang Zhu for providing valuable reagents. We thank Maarten van Lohuizen, Pier Giuseppe Pelicci, Chris Marine and members of the Helin laboratory for discussions. We thank Luciano di Croce and Claire Attwooll for critical reading of the manuscript. This work was supported by grants from AIRC, FIRC, The European Union Fifth Framework Program, The Italian Health Ministry and the Human Science Frontiers Science Program.

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Author notes

  1. A.P.Bracken and D.Pasini contributed equally to this work

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy

    Adrian P. Bracken, Diego Pasini, Maria Capra, Elena Prosperini, Elena Colli & Kristian Helin

  2. FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy

    Maria Capra & Kristian Helin

Authors
  1. Adrian P. Bracken
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  2. Diego Pasini
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Correspondence to Kristian Helin.

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Bracken, A.P., Pasini, D., Capra, M. et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22, 5323–5335 (2003). https://doi.org/10.1093/emboj/cdg542

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