Article

Regulation of Tumor Angiogenesis by EZH2

Department of Gynecologic Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer cell (Impact Factor: 23.89). 08/2010; 18(2):185-97. DOI: 10.1016/j.ccr.2010.06.016
Source: PubMed

ABSTRACT Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.

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Available from: Robert L Coleman, Sep 01, 2015
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    • "In addition, several molecules such as Bim, TRAIL, and FBXO32 play a role in apoptosis induced by the inhibition of EZH2 [138-140]. Vasohibin1 is regulated by EZH2 in tumor-associated endothelial cells, and this regulation plays a role in tumor angiogenesis [141]. EZH2 also regulates the expression other epigenetic regulators by silencing multiple miRNAs, which are critical for the oncogenic function of EZH2 [142,143]. "
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    ABSTRACT: Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.
    Cancer Research and Treatment 07/2014; 46(3):209-222. DOI:10.4143/crt.2014.46.3.209 · 2.98 Impact Factor
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    • "Angiogenesis is required for invasive tumor growth and metastasis. A recent study showed that EZH2 is a key regulator of tumor angiogenesis through its expression in cancer associated endothelial cells in human ovarian cancer [39]. Interestingly, we observed a visible evidence for the loss of angiogenesis in the EZH2 knockdown tumors (Figure 4A and B). "
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    ABSTRACT: Inflammatory breast cancer (IBC) is the most metastatic variant of breast cancer with the poorest survival in all types of breast cancer patients and presently therapeutic targets for IBC are very limited. Enhancer of zeste homolog 2 (EZH2) is frequently expressed in human IBC and its expression positively correlates with worse clinical outcome. However, the molecular basis for EZH2 promoting IBC has not been explored. Here, we investigated the functional role of EZH2 in IBC cells by examining the effects of its knockdown on the formation of tumor spheroids and invasion of these cells in vitro and in vivo in an orthotopic xenograft model. SUM149 and a new IBC cell line-FC-IBC-02 derived from pleural effusion fluid of an IBC patient were used in this study. Specific knockdown of EZH2 was performed using short hairpin RNA (shRNA) specific to the human EZH2 gene. Cell growth and the formation of tumor spheroids were examined in vitro. The effects of EZH2 knockdown on IBC cell migration and invasion were examined by a Boyden chamber assay. For the in vivo tumor growth studies, IBC cells were orthotopically transplanted into the mammary fat pads of immunodeficient mice. The results showed that EZH2 is expressed at higher levels in human IBC cell lines compared with normal human mammary epithelial cells, and the knockdown of EZH2 expression significantly suppressed cell growth and tumor spheroid formation of human IBC cells in vitro. In addition, EZH2 knockdown inhibited the migration and invasion of IBC cells. Significantly, EZH2 knockdown suppressed the angiogenesis and tumor growth of IBC cells in vivo. Our results provide direct evidence that EZH2 is critical for the formation of tumor spheroids and invasion of human IBC cells and could be a potential target for developing novel therapeutic strategies for human IBC.
    Journal of Experimental & Clinical Cancer Research 09/2013; 32(1):70. DOI:10.1186/1756-9966-32-70 · 4.23 Impact Factor
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    • "Alternatively, with regard to its function, we showed that increased tumor growth and tumor angiogenesis were evident when Lewis lung carcinoma (LCC) cells were inoculated into VASH1 (−/−) mice [12]. Indeed, decreased expression of VASH1 correlated with poor prognosis of certain human cancers [21], [22]. These observations suggest that endogenous VASH1 regulates the course of tumor angiogenesis and tumor progression. "
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    ABSTRACT: Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium. We previously reported that tumor growth and tumor angiogenesis were augmented in VASH1 (-/-) mice. Here we examined whether VASH1 plays any role in cancer metastasis. When Lewis lung carcinoma (LLC) cells were inoculated in the footpad to observe spontaneous metastasis, a significant increase in lung metastasis together with inguinal lymph node metastasis was evident in the VASH1 (-/-) mice. Histological analyses revealed that vessels of the footpad tumor in VASH1 (-/-) mice were more immature, having fewer mural cells. However, when LLC cells were injected into a tail vein, the extent of lung metastasis was unchanged between wild-type mice and VASH1 (-/-) mice. When VASH1 in endothelial cells in culture was knocked-down by siRNA, we observed a decrease in the content of ZO-1, a component of tight junctions, which decrease resulted in increased transmigration of cancer cells across the endothelial cell monolayer. These results indicate that endogenous VASH1 tightens the endothelial barrier and makes tumor vessels resistant to cancer metastasis.
    PLoS ONE 09/2013; 8(9):e73931. DOI:10.1371/journal.pone.0073931 · 3.23 Impact Factor
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