The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer

Zeidler, Michael G.; Kleer, Celina G.

doi:10.1007/s10735-006-9042-9

Cited by 33 publications

(30 citation statements)

References 32 publications

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“…[23][24][25] Recently, several studies have also shown EZH2 to be highly expressed in aggressive tumors, including human breast cancer, prostate cancer and lymphomas. 9,[13][14][15]26,27 The present study showed PcG proteins Bmi1 and EZH2 which are epigenetic chromatin modifier involved in cancer development, 7 to be involved in this malignant progression of HCC. PcGs are chromatin modifiers which have been reported to affect the expression of a number of genes.…”

Section: Discussionmentioning

confidence: 55%

“…16 EZH2 was not expressed in either the cholangiocyte or hepatocytes in non-tumorous livers, it is conceivable that the EZH2 expression in addition to the Bmi1 expression may therefore be a predictor of the biological aggressiveness and poor prognosis in HCC and HC-CC as reported in carcinomas in other organs. 9,[13][14][15]26,27,29 Since the extensive expression of Bmi1 and EZH2 was demonstrated in HCC and HC-CC, especially in an aggressive subgroup, Bmi1 and EZH2 may therefore be an effective therapeutic target molecule for advanced HCC and HC-CC. The findings of both the present study and several previous studies showed that the knockdown of Bmi1 and EZH2 using siRNA can induce growth inhibition while reducing metastasis.…”

Section: Discussionmentioning

confidence: 99%

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The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Sasaki

Ikeda

Itatsu

et al. 2008

Laboratory Investigation

121

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Polycomb-group proteins Bmi1 and EZH2 are involved in the malignant transformation and biological aggressiveness of several human carcinomas. We herein examined the significance of the Bmi1 and EZH2 expression in hepatocellular carcinoma (HCC) and its preneoplastic lesions, dysplastic nodules. The expression of Bmi1 and EZH2 were examined immunohistochemically in HCC (n ¼ 27) and dysplastic nodules (n ¼ 14), and combined hepatocellular and cholangiocarcinoma (HC-CC) (n ¼ 14). The effect of Bmi1 and EZH2 knockdown was examined in cultured HCC cells (HuH7 and HepG2) using siRNA. It was determined that Bmi1 was constantly expressed in cholangiocytes, but not in hepatocytes, and EZH2 was detected in neither cholangiocytes nor hepatocytes. Bmi1 and EZH2 were overexpressed in HCC and more extensively in HC-CC (Po0.01). Interestingly, Bmi1 and EZH2 were not overexpressed in the dysplastic nodules. The expression of Bmi1 and EZH2 was heterogeneous and associated with vascular infiltration, the histological grades, and the cell proliferation activity in HCC and HC-CC. In cultured carcinoma cells overexpressing Bmi1 and EZH2, knockdown of Bmi1 and EZH2 resulted in decreased cell proliferation activities. Therefore, the overexpression of polycomb-group proteins Bmi1 and EZH2 is associated with the malignant progression of HCC, thereby reflecting the aggressive biological behavior in HCC and HC-CC.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Sasaki

Ikeda

Itatsu

et al. 2008

Laboratory Investigation

121

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“…Ezh2 (polycomb group protein enhancer of zeste homolog 2) is the histone methyltransferase catalytic subunit of the polycomb-repressive complex 2, being overexpressed in a variety of aggressive breast cancers (28,29). Ezh2 is associated with genome instability, disruption of mammary ductal morphogenesis (30), and invasion and metastasis of malignant breast cancer, being partly accounted for by suppression of E-cadherin and induction of MMPs expression (31,32). Ezh2 transcript, protein, and cell content Ã , significant as compared with control diet (P < 0.05); ÃÃ , significant as compared with control diet (P < 0.002).…”

Section: Mmtv-pymt Mesenchymal-epithelial Transition In Response To Mmentioning

confidence: 99%

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

et al. 2014

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Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither b-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydraterestricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src-transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction. Cancer Res; 74(23); 6991-7002. Ó2014 AACR.

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“…Histone H3, one of the five main histone proteins, is a chromatin structural component found in eukaryotic cells (Bhasin et al, 2006). Increasing the levels of H3K27me3 may contribute to the aggressiveness of cancer in various tumors like brain (Smits et al, 2010), breast (Zeidler et al, 2006;Kleer, 2009), kidney (Wagener et al, 2008), lung (Crea et al, 2011), lymphoma (Be´guelin et al, 2013;Yan et al, 2013), and prostate (Takawa et al, 2011). As EZH2 inhibition may lead to transcriptional repression of the affected target gene, the development of potent EZH2 inhibitors has become an attractive therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies

Kumar

Lightner

et al. 2015

MRAJ

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Abstract-Histone lysine methyl transferase 2 (EZH2) inhibitor GSK126 and a novel deuterated internal standard GSK126-d7 were chemically prepared. We performed in vitro experiments using the prepared GSK126 to: i) confirm in vitro EZH2 inhibitory activity; ii) conduct SpragueDawley (SD) rat liver microsomal incubations and identified Phase I metabolites; iii) determine whether or not GSK126 was an Organic Anion Transporter (OAT) substrate; and, iv) determine oral bioavailability by conducting oral and orbital sinus dosing (OSD) experiments and determining blood concentration versus time profiles. GSK126 was shown to decrease the expression of H3K27Me3 protein in medulloblastoma D283 cells and was able to decrease cell viability in KO99L cells, a novel T cell lymphoma cell line. Three in vitro hepatic Phase I monooxidative metabolites (L-M1, L-M2 and L-M3) were observed and also detected in rat liver and urine samples from the in vivo studies. GSK126 was found to be an OAT1 and OAT2 substrate, but not an OAT3 or OAT4 substrate. Our Pharmacokinetic (PK) results indicate: 1) GSK126 has very poor oral bioavailability (< 2%); 2) co-administration of probenecid, a prototypical OAT inhibitor, did not significantly alter observed PK; and 3) tissue distribution studies demonstrate that GSK126 predominately distributes to the liver and kidneys after an OSD.

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The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer

Cited by 33 publications

References 32 publications

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies

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