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EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis

机译：EZH2抑制：靶向肿瘤侵袭和血管生成的十字路口

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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.
机译：肿瘤血管生成和转移扩散是两个高度相关的现象，它们导致与癌症相关的死亡。因此，确定靶向血管生成和转移性扩散的新策略至关重要。聚梳基因是一组表观遗传效应子，结构化为多聚体阻遏复合物。 EZH2是Polycomb阻抑复合物2（PRC2）的催化亚基，它使组蛋白H3赖氨酸27甲基化，从而沉默了几个抑癌基因。 EZH2对于癌症干细胞自我更新至关重要。有趣的是，癌症干细胞被认为是转移扩散的种子，并且能够分化为肿瘤相关的内皮细胞。临床前研究表明，EZH2能够沉默多个抗转移基因（例如E-钙粘蛋白和金属蛋白酶的组织抑制剂），从而促进细胞侵袭和不依赖锚定的生长。另外，EZH2似乎在调节肿瘤血管生成中起关键作用。 EZH2高表达预示了几种癌症类型的不良预后，高等级和高分期。最近，PRC2的小分子抑制剂（DZNeP）在体外和体内均显示出有希望的抗肿瘤活性。有趣的是，DZNeP能够分别抑制前列腺癌和脑癌中的癌细胞侵袭和肿瘤血管生成。在抑制肿瘤的剂量下，DZNeP对未转化的细胞无害。在本手稿中，我们回顾了支持EZH2在转移性扩散和肿瘤血管生成中作用的当前证据。使用Oncomine数据集，我们显示DZNeP目标在某些转移性癌症中被特异地沉默，其中一些可能抑制血管生成。基于这一证据，我们建议开发EZH2抑制剂作为抗血管生成和抗转移疗法。

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