Poorly Differentiated Breast Carcinoma is Associated with Increased Expression of the Human Polycomb Group EZH2 Gene

Raaphorst, Frank M.; Meijer, Chris J.L.M.; Fieret, Elly; Blokzijl, Tjasso; Mommers, Ellen C.M.; Buerger, Horst; Packeisen, J; Sewalt, Richard A.B.; Ottet, Arie P.; Diest, Paul J. van

doi:10.1016/s1476-5586(03)80032-5

Cited by 173 publications

(155 citation statements)

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“…Consistent with recent studies demonstrating overexpression of PcG genes in cancer (Vonlanthen et al, 2001;Sellers and Loda, 2002;Kleer et al, 2003;Raaphorst et al, 2003;Breuer et al, 2004;Kim et al, 2004;Shi et al, 2005), we found that both BMI-1 and EZH2 are strongly expressed by a variety of tumours (Table 3; Supplementary Material; Figure 1). This broad upregulation in cancer makes them attractive immunotherapeutic targets for malignant disease.…”

Section: Discussionsupporting

confidence: 91%

“…High-level expression of EZH2 mRNA was observed in the prostate cancer cell line LNCaP, the HepG2 hepatoblastoma cell line and three breast cancer cell lines MCF7, BT549 and nDA-MB436. This confirms previous studies demonstrating upregulation of EZH2 expression in tumours of patients with breast cancer (Kleer et al, 2003;Raaphorst et al, 2003;Kim et al, 2004). Variable expression was seen in a number of EBV-transformed LCL, with low expression of EZH2 mRNA in the cervical carcinoma cell line Caski, and in normal fibroblasts ( Figure 1B).…”

Section: Expression Of Bmi-1 and Ezh2 In Normal And Tumour Tissuesupporting

confidence: 91%

“…Aberrant PcG protein expression, such as overexpression, failure of downregulation or coexpression, has been reported in Hodgkin's lymphoma , B-cell lymphoma , mantle cell lymphoma (Bea et al, 2001;Visser et al, 2001), prostate cancer (Sellers and Loda, 2002;Varambally et al, 2002), breast carcinoma (Kleer et al, 2003;Raaphorst et al, 2003;Kim et al, 2004), HCC (Shi et al, 2005) and during lung carcinogenesis (Vonlanthen et al, 2001;Breuer et al, 2004). Some of these altered patterns of expression may be of diagnostic and prognostic relevance (Varambally et al, 2002;Raaphorst et al, 2003;Breuer et al, 2004;Kim et al, 2004). Our study shows that BMI-1 and EZH2 are overexpressed in several epithelial tumours and that both proteins are associated with both humoral and T-cell responses, suggesting that they represent a novel family of TAAs that might be potential targets for immunotherapy.…”

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confidence: 99%

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The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Steele

Torr

Noakes³

et al. 2006

Br J Cancer

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We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8 þ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-g (IFN-g) release than BMI-1-derived peptides. That CD8 þ T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-g capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666 -674) epitope. The ability of YMSCSFLFNL (aa 666 -674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25 þ T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

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Section: Discussionsupporting

confidence: 91%

Section: Expression Of Bmi-1 and Ezh2 In Normal And Tumour Tissuesupporting

confidence: 91%

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confidence: 99%

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The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Steele

Torr

Noakes³

et al. 2006

Br J Cancer

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“…Examples are ERa, 10,32 the transcription factor TP53, 7-9,33 its negative regulator MDM2 4,34,35 and the polycomb group protein EZH2. 36,37 In summary, in this first study on genetic variation in UBC9 and breast cancer progression, we found associations of rs7187167, rs11248866 and rs8052688, and tumor grade. The strongest association was found for rs7187167.…”

Section: Discussionmentioning

confidence: 59%

Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade

Dünnebier¹,

Bermejo²,

Haas³

et al. 2009

Intl Journal of Cancer

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UBC9 encodes a protein that conjugates small ubiquitin-related modifier (SUMO) to target proteins resulting in a change of their localization, activity or stability. Genetic variability may affect expression and activity of UBC9 and may have an impact on breast tumor progression. We investigated associations between UBC9 genotypes and histopathological parameters in 1,021 breast cancer cases of the GENICA collection using a single nucleotide polymorphism (SNP) tagging approach. Genotyping analyses were performed by TaqMan 1 allelic discrimination. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by ordinal logistic regression. Multiple imputation based on HapMap data was applied to boost the power of the study. The study revealed significant associations of three UBC9 SNPs with histological grade (rs7187167, p trend 5 0.001; rs11248866, p trend 5 0.009; rs8052688, p trend 5 0.008). Model selection identified a recessive penetrance model for rs7187167 as the best representation of tumor grade (global p 5 0.001). This model did not improve by inclusion of additional SNPs in linkage disequilibrium. Imputation of SNPs in a 300 kb region around the genotyped SNPs supported rs7187167 as a major contributor to tumor grade. Compared with common allele carriers, rare homozygotes presented less frequently with high grade tumors (G3 vs. G1: OR 0.26, 95% CI 0.11-0.62; G3 vs. G2: OR 0.45, 95% CI 0.23-0.86). In addition to tumor size, nodal status and estrogen receptor status, multivariate analyses confirmed an independent role of rs7187167 as predictor of tumor grade (p 5 0.0003). The present results underline the value of genetic variation in UBC9 for breast cancer prognosis. ' 2009 UICC Key words: UBC9 polymorphisms; SUMOylation; breast cancer progression; tumor grade; multiple imputation Rapid and reversible post-translational protein modifications including phosphorylation, methylation, acetylation, glycosylation and ubiquitination are key elements in the regulation of many cellular processes. Another recently identified type of modification is small ubiquitin-related modifier (SUMO) conjugation or SUMOylation. SUMO plays an important role in the regulation of physical interactions. 1,2 By masking or adding interaction surfaces or by inducing conformational changes, it governs proteinprotein and protein-DNA interactions and in consequence can lead to changes in protein localization, activity or stability. Substrates of SUMO participate in diverse cellular processes, including transcriptional regulation, nuclear transport, cell cycle control and maintenance of genome integrity. SUMOylation is a multistep process involving maturation, activation and conjugation. 3 The SUMO-conjugating enzyme UBC9 (UBE2I) is essential for SUMOylation and transfers the activated SUMO to the target protein. This transfer is facilitated by SUMO ligases such as the protein inhibitors of activated STAT (PIAS) family proteins that together with UBC9 confer substrate specificity. 2 Due to the existence of SUMO isopeptidases, SUM...

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“…[14][15][16][17][18] EZH2 is expressed in undifferentiated stem-like cancer cells and promotes cancer cell proliferation and metastasis formation by repressing several tumor suppressor genes. 15,[19][20][21][22][23][24] Notably, its molecular or pharmacological inhibition leads to the reversal of the malignant phenotype.…”

Section: Introductionmentioning

confidence: 99%

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

et al. 2013

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The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.Oncogene ( Keywords: EZH2; FBXO32; histone methyltransferases; PAX3-FOXO1; rhabdomyosarcoma; Polycomb proteins INTRODUCTION Rhabdomyosarcomas (RMS) are heterogeneous highly malignant tumors, which account for 7-8% of all pediatric malignancies and over half of the soft-tissue sarcomas in children. RMS are classically subdivided in two major histotypes: embryonal (around 70-80%) and alveolar (around 20-30%), the latter often metastatic at diagnosis and showing a high risk of recurrence. 1 In 70% of cases, alveolar RMS is characterized by the chromosomal translocation t(2;13) or t(1;13), resulting in

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Poorly Differentiated Breast Carcinoma is Associated with Increased Expression of the Human Polycomb Group EZH2 Gene

Cited by 173 publications

References 50 publications

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Common variants in the UBC9 gene encoding the SUMO‐conjugating enzyme are associated with breast tumor grade

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

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