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EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis

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Abstract

Tumor angiogenesis and metastatic spreading are two highly interconnected phenomena, which contribute to cancer-associated deaths. Thus, the identification of novel strategies to target angiogenesis and metastatic spreading is crucial. Polycomb genes are a set of epigenetic effectors, structured in multimeric repressive complexes. EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 lysine 27, thereby silencing several tumor-suppressor genes. EZH2 is essential for cancer stem cell self-renewal. Interestingly, cancer stem cells are thought to be the seeds of metastatic spreading and are able to differentiate into tumor-associated endothelial cells. Pre-clinical studies showed that EZH2 is able to silence several anti-metastatic genes ( e.g., E-cadherin and tissue inhibitors of metalloproteinases), thereby favoring cell invasion and anchorage-independent growth. In addition, EZH2 seems to play a crucial role in the regulation of tumor angiogenesis. High EZH2 expression predicts poor prognosis, high grade, and high stage in several cancer types. Recently, a small molecule inhibitor of PRC2 (DZNeP) demonstrated promising anti-tumor activity, both in vitro and in vivo. Interestingly, DZNeP was able to inhibit cancer cell invasion and tumor angiogenesis in prostate and brain cancers, respectively. At tumor-inhibiting doses, DZNeP is not harmful for non-transformed cells. In the present manuscript, we review current evidence supporting a role of EZH2 in metastatic spreading and tumor angiogenesis. Using Oncomine datasets, we show that DZNeP targets are specifically silenced in some metastatic cancers, and some of them may inhibit angiogenesis. Based on this evidence, we propose the development of EZH2 inhibitors as anti-angiogenic and anti-metastatic therapy.

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Acknowledgments

This work has been supported, in part, by AIRC (Associazione Italiana per la Ricerca sul Cancro) to Guido Bocci and by MIUR-PRIN2008 project 20084TASKL_004: “Epigenetic manipulation and reversal of resistance to irinotecan in human colorectal cancer cell lines” to Romano Danesi.

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Authors and Affiliations

  1. Division of Pharmacology, Department of Internal Medicine, University of Pisa, via Roma 55, 56126, Pisa, Italy

    Francesco Crea, Guido Bocci & Romano Danesi

  2. Division of Medical Oncology, Transplants and New Technologies in Medicine, Department of Oncology, University of Pisa, via Roma 67, 56126, Pisa, Italy

    Lorenzo Fornaro & Alfredo Falcone

  3. Institute for Life Sciences, Scuola Superiore di Studi Universitari e di Perfezionamento Sant’Anna, P.zza Martiri della Libertà 33, 56127, Pisa, Italy

    Lorenzo Fornaro

  4. Istituto Toscano Tumori, via Alderotti 27/n, 50139, Firenze, Italy

    Guido Bocci

  5. Cancer Stem Cell Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Lei Sun & William L. Farrar

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  1. Francesco Crea
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Correspondence to Guido Bocci.

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Crea, F., Fornaro, L., Bocci, G. et al. EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis. Cancer Metastasis Rev 31, 753–761 (2012). https://doi.org/10.1007/s10555-012-9387-3

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