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Cancer and Metastasis Reviews
Published in: Cancer and Metastasis Reviews 3-4/2012

01-12-2012 | NON-THEMATIC REVIEW

EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis

Authors: Francesco Crea, Lorenzo Fornaro, Guido Bocci, Lei Sun, William L. Farrar, Alfredo Falcone, Romano Danesi

Published in: Cancer and Metastasis Reviews | Issue 3-4/2012

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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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Metadata
Title
EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis
Authors
Francesco Crea
Lorenzo Fornaro
Guido Bocci
Lei Sun
William L. Farrar
Alfredo Falcone
Romano Danesi
Publication date
01-12-2012
Publisher
Springer US
Published in
Cancer and Metastasis Reviews / Issue 3-4/2012
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-012-9387-3

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