Polycomb-Group Oncogenes EZH2, BMI1, and RING1 Are Overexpressed in Prostate Cancer With Adverse Pathologic and Clinical Features

Leenders, Geert J.L.H. van; Dukers, Danny F.; Hessels, Daphne; Kieboom, Susan W.M. van den; Hulsbergen, C.; Witjes, J.A.; Otte, Arie P.; Meijer, Chris J.L.M.; Raaphorst, Frank M.

doi:10.1016/j.eururo.2006.11.020

Cited by 170 publications

(143 citation statements)

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“…There is a general consensus that EZH2 overexpression aggravates during prostate cancer progression. In metastases, even gene amplification is found and associated with strong overexpression, 42 whereas the increases in primary cases are usually moderate, 24,40,44 as in the present study, or are even undetectable. 25 However, the moderate increases in nonmetastatic cancers might be difficult to detect by the RNA-in-situ-hybridization technique used in ref.…”

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confidence: 54%

“…In accord with its relationship to progression, EZH2 overexpression in primary cancers is typically associated with risk of metastasis and recurrence. 24,40 In the present study, this …”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 95%

“…Very recently, two studies have appeared linking increased BMI-1 expression to prostate cancer progression and metastasis, one even reporting gene amplification in metastatic cases, as for EZH2. 41 The second study 40 employed immunohistochemistry-using the same antibody as in the present investigation. Accordingly, both studies detected strong BMI-1 staining in normal prostate epithelium and Figure 2 in van Leenders et al 40 even reveals the same heterogeneity in tumors we observed.…”

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confidence: 99%

“…Its expression increases gradually during prostate cancer progression and is maximal in metastatic cases. 24,[40][41][42][43][44] Despite numerous descriptive studies, the effects of EZH2 overexpression in prostate cancer are poorly understood. On BMI-1, only two, very recent studies 40,41 have been published and none on SIRT1 in human cancers.…”

Section: Introductionmentioning

confidence: 99%

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Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

Hoffmann

Engers

Florl³

et al. 2007

Cancer Biology & Therapy

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The polycomb proteins BMI-1, EZH2 and SIRT1 are characteristic components of the PRC1, PRC2 and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate cancer progression, whereas BMI-1 and SIRT1 are not well investigated. Like EZH2 expression, DNA methylation alterations escalate in higher stage prostate cancers, raising the question whether these epigenetic changes are related. Expression of EZH2, BMI-1, SIRT1 and the DNA methyltransferases DNMT1 and DNMT3B measured by qRT-PCR in 47 primary prostate cancers was compared to APC, ASC, GSTP1, RARB2 and RASSF1A hypermethylation and LINE-1 hypomethylation. SIRT1 and DNMT3B were overexpressed in cancerous over benign tissues, whereas BMI-1 was rather downregulated and DNMT1 significantly diminished. Nevertheless, cancers with higher DNMT1 and BMI-1 expression had worse clinical characteristics, as did those with elevated EZH2. In particular, above median DNMT1 expression predicted a worse prognosis. EZH2 and SIRT1 overexpression were well correlated with increased MKI67. Immunohistochemistry confirmed limited EZH2 and heterogeneous DNMT3B overexpression and explained the decrease in BMI-1 by pronounced heterogeneity among tumor cells. EZH2 overexpression, specifically among all factors investigated, was associated with more frequent hypermethylation, in particular of GSTP1 and RARB2 and also with LINE-1 hypomethylation. Our data reveal complex changes in the composition of polycomb repressor complexes in prostate cancer. Heterogeneously expressed BMI-1 and slightly increased EZH2 may characterize less malignant cancers, whereas more aggressive cases express both at higher levels. SIRT1 appears to be generally increased in prostate cancers. Intriguingly, our data suggest a direct influence of increased EZH2 on altered DNA methylation patterns in prostate cancer.

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confidence: 54%

“…In accord with its relationship to progression, EZH2 overexpression in primary cancers is typically associated with risk of metastasis and recurrence. 24,40 In the present study, this …”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 95%

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

Hoffmann

Engers

Florl³

et al. 2007

Cancer Biology & Therapy

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“…To date, the proto-oncogene Bmi-1 has been reported to be up-regulated in a large number of neoplasias, namely in lymphomas [27], cerebral tumours [26], breast cancer [13] and other epithelial tumours [28,29] and to be an oncogene associated with poor prognosis in various tumours [12]. To investigate whether or not the abnormal expression of Bmi-1 is involved in the pathogenesis of ovarian carcinoma, in the present study, the protein expression of Bmi-1 was examined firstly by IHC in normal ovaries, benign and borderline epithelial ovarian tumors, and malignant epithelial cancers.…”

Section: Discussionmentioning

confidence: 99%

Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma

Yang

Cai

et al. 2010

BMC Cancer

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BackgroundIt has been suggested that the B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays an oncogenic role in several types of human cancer, but the status of Bmi-1 amplification and expression in ovarian cancer and its clinical/prognostic significance are unclear.MethodsThe methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of Bmi-1 in 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors and 179 ovarian carcinomas.ResultsIntensive expression of Bmi-1 was detected in none of the normal ovaries, 3% cystadenomas, 10% borderline tumors, and 37% ovarian carcinomas, respectively. Amplification of Bmi-1 was detected in 8% of ovarian carcinomas. In ovarian carcinomas, significant positive associations were found between intensive expression of Bmi-1 and the tumors ascending histological grade, later pT/pN/pM and FIGO stages (P < 0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of Bmi-1 with shortened patient survival (mean 49.3 months versus 100.3 months, p < 0.001) was demonstrated. Importantly, Bmi-1 expression provided significant independent prognostic parameters in multivariate analysis (p = 0.005).ConclusionsThese findings provide evidence that intensive expression of Bmi-1 might be important in the acquisition of an invasive and/or aggressive phenotype of ovarian carcinoma, and serve as a independent biomarker for shortened survival time of patients.

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Polycomb group protein EZH2 is frequently expressed in inflammatory breast cancer and is predictive of worse clinical outcome

Gong

Huo

Liu

et al. 2011

Cancer

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BACKGROUND: Enhancer of zeste homolog 2 (EZH2), a member of polycomb group proteins, is involved in the regulation of cell cycle progression and has been implicated in various human malignancies, including breast cancer, and also has been associated with aggressive tumor behavior. However, the clinical significance of EZH2 expression in inflammatory breast cancer (IBC), a rare but aggressive type of breast carcinoma, has not been explored. In this retrospective study, the authors examined EZH2 expression in IBC tumors and evaluated the relation between EZH2 expression and patient survival. METHODS: Tissue microarrays of 88 surgically resected IBC tumors were stained immunohistochemically for EZH2, and the authors evaluated the association of EZH2 expression status with clinicopathologic factors and clinical outcome. RESULTS: The median follow-up for the entire cohort was 45.7 months, and the 5-year overall survival (OS) rate was 45%. EZH2 was expressed frequently in IBC tumors (75.7%) and was associated significantly with unfavorable prognostic factors, such as higher tumor grade, negative estrogen receptor status, and triple-negative status (ie, negative for the estrogen, progesterone, and human epidermal growth factor 2 receptors). Univariate survival analysis indicated that patients who had EZH2-positive IBC had a significantly lower 5-year OS rate than patients who had EZH2-negative IBC (P ¼ .01). In multivariate analysis, only positive EZH2 status remained an independent predictor of worse OS. CONCLUSIONS: EZH2 was expressed frequently in IBC tumors. The current results indicated that EZH2 expression status may be used to identify a subset of patients with IBC who have a relatively worse prognosis. Targeting EZH2 also may provide a novel strategy for improving the clinical outcome of patients with IBC. Cancer 2011;117:5476-

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Polycomb-Group Oncogenes EZH2, BMI1, and RING1 Are Overexpressed in Prostate Cancer With Adverse Pathologic and Clinical Features

Cited by 170 publications

References 27 publications

Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma

Polycomb group protein EZH2 is frequently expressed in inflammatory breast cancer and is predictive of worse clinical outcome

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