Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

Tonini, Tiziana; Bagella, Luigi; D’Andrilli, Giuseppina; Claudio, Pier Paolo; Giordano, Antonio

doi:10.1038/sj.onc.1207608

Cited by 69 publications

(67 citation statements)

References 52 publications

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“…EZH2 expression has also been demonstrated to have prognostic significance in patients with prostate cancer (Sellers and Loda, 2002;Varambally et al, 2002;Rhodes et al, 2003;Foster et al, 2004). Therefore, the role of EZH2 in tumour development and progression has recently become a subject of increased interest (Tonini et al, 2004). To the best of our knowledge, however, the clinicopathological and prognostic significance of the EZH2 geneexpression status has not previously been examined in digestive organ cancers.…”

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confidence: 88%

Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma

et al. 2005

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Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group protein family, plays a crucial role in the regulation of embryonic development and has been associated with the regulation of the cell cycle. Recently, several studies have shown that EZH2 is highly expressed in aggressive tumours, including human breast cancer, prostate cancer, and lymphomas. We thus analysed EZH2 expression using real-time reverse transcription -polymerase chain reaction, and correlated its expression status with various clinicopathological parameters in 66 patients with hepatocellular carcinoma (HCC). We found high expression of EZH2 in human liver cancer cell lines. Furthermore, EZH2 gene-expression levels in tumour tissue specimens (0.3470.52) were significantly higher (Po0.0001) than those in the corresponding nontumour tissue specimens (0.0770.09). The incidence of cancer cell invasion into the portal vein was significantly higher (Po0.001) in the high EZH2 expression group (26 of the 33, 79%) than in the low expression group (13 of the 33, 39%). However, there was no significant difference in the disease-free survival rate between the two groups. The findings of this study indicate that EZH2 mRNA expression was upregulated in human HCC and may play an important role in tumour progression, especially by facilitating portal vein invasion. British Journal of Cancer (2005) Polycomb group (PcG) proteins are known to maintain the silenced state of several developmentally regulated genes and to control the transcriptional memory of a cell (Laible et al, 1997;van der Vlag et al, 1999). Dysregulation of this gene-silencing machinery may lead to cancer (Jacobs et al, 1999;Satijin and Otte, 1999). Recently, enhancer of zeste homologue 2 (EZH2), a member of the PcG protein family, has been linked to the aggressiveness of human cancers, including lymphomas ) provided biological evidence that overexpression of EZH2 promotes oncogenic transformation. In breast epithelial cells, they observed that high expression of EZH2 induced anchorage-independent growth and cell invasion, behaviours that are hallmarks of cancer. Moreover, they found that higher expression levels of EZH2 protein were strongly associated with decreased disease-free survival and decreased overall survival for patients with breast cancer. In addition, Varambally et al (2002) reported that EZH2 was overexpressed in metastatic prostate cancer and that inhibition of EZH2 blocked prostate cell growth. EZH2 expression has also been demonstrated to have prognostic significance in patients with prostate cancer (Sellers and Loda, 2002;Varambally et al, 2002;Rhodes et al, 2003;Foster et al, 2004). Therefore, the role of EZH2 in tumour development and progression has recently become a subject of increased interest (Tonini et al, 2004). To the best of our knowledge, however, the clinicopathological and prognostic significance of the EZH2 geneexpression status has not previously been examined in digestive organ cancers. The present study thus focused on examining the relationsh...

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confidence: 88%

Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma

et al. 2005

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“…The MEIS1-HOXA9 interaction has been reported to rapidly accelerate leukemogenesis in mice (30 -32), making these proteins and their interaction a potential therapeutic target for further evaluation. Additionally, in the PRC2 complex, EZH2 is known to interact with histone deacetylases (HDAC) 1 and 2 through the EED protein (13,33,34). This suggests that based on the cellular context, the transcriptional repression by the PRC2 complex may be mediated through the activity of the HDACs (18).…”

Section: Introductionmentioning

confidence: 99%

“…This can promote cellular transformation and confer invasiveness in immortalized breast epithelial cells (16). With SUZ12 and EED, EZH2 has been established as the minimum functional PRC2 core complex exerting gene silencing through methylation of H3K27 and is transcriptionally regulated by the pRB/E2F pathway (3,13,19). Activated p53 has also been shown to suppress EZH2 expression (20).…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

Fiskus¹,

Pranpat²,

Balasis³

et al. 2006

Molecular Cancer Therapeutics

103

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Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes.

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“…The uniform expression of the EZH2 gene in cell lines is not surprising, since many studies have found EZH2 to stimulate cell proliferation and cell-cycle progression. 21,22,40,41 This may also explain the EZH2 transcript observed in testes, a highly proliferating tissue. However, EZH2 expression in proliferating cells and tissues raises concern with regards to the specificity of an EZH2-promoter-regulated suicide gene construct.…”

Section: Discussionmentioning

confidence: 97%

A chimeric fusion of the hASH1 and EZH2 promoters mediates high and specific reporter and suicide gene expression and cytotoxicity in small cell lung cancer cells

et al. 2008

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Transcriptionally targeted gene therapy is a promising experimental modality for treatment of systemic malignancies such as small cell lung cancer (SCLC). We have identified the human achaete-scute homolog 1 (hASH1) and enhancer of zeste homolog 2 (EZH2) genes as highly upregulated in SCLC compared to a panel of representative normal tissues. Here, we evaluate the use of regulatory regions from the hASH1-and EZH2-promoter regions alone and in combination for suicide gene therapy of SCLC. Two hASH1-promoter regions comprising 0.3 and 0.7 kb immediately upstream of (and including) the transcription start site were tested. Both constructs induced reporter gene activity (up to sevenfold SV40-promoter activity) in all tested classic (hASH1 positive) SCLC and in two hASH1-negative SCLC cell lines, whereas gene activity was low or absent (o4% of SV40 activity) in one hASH1-negative SCLC and in all control cell lines tested. To evaluate its therapeutic potential, the 0.7 kb hASH1 proximal-promoter region was evaluated for cytotoxicity in a suicide gene assay. The construct induced SCLC cytotoxicity at levels equivalent to those observed with the SV40 promoter, while control cells remained unaffected by the treatment. Analogously, a 1.1 kb EZH2-promoter region was evaluated by reporter and suicide gene assays. The EZH2 promoter potently induced reporter gene activity in SCLC (up to 25-fold of SV40 activity) while moderate reporter activity (up to 12% of SV40 activity), was detected in the control cells. However, in the suicide gene assay both control and SCLC cells demonstrated sensitivity indicating lack of promoter specificity. Finally, we fused the 0.7 kb hASH1 promoter to the EZH2 promoter generating a chimeric hASH1EZH2 regulatory construct. The chimeric promoter demonstrated increased activity in SCLC cells compared to the hASH1 promoter alone while retaining specificity in control cells. The hASH1EZH2 promoter thus constitutes a promising transcriptional regulator for SCLC gene therapy.

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Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A

Cited by 69 publications

References 52 publications

Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma

Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

A chimeric fusion of the hASH1 and EZH2 promoters mediates high and specific reporter and suicide gene expression and cytotoxicity in small cell lung cancer cells

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