The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma

Visser, Hein P.J.; Gunster, M.J.; Kluin-Nelemans, Hanneke C.; Manders, Erik M. M.; Raaphorst, Frank M.; Meijer, Chris J.L.M.; Willemze, R.; Otte, Arie P.

doi:10.1046/j.1365-2141.2001.02641.x

Cited by 213 publications

(157 citation statements)

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“…20 Studies of PcG in human tissues show that this system plays important roles in several biological functions, such as regulation of cell differentiation, 16,18,21,22 hematopoietic and neural stem cell self-renewal [23][24][25] and control of cellular proliferation. 3,17,18,21,[26][27][28][29] The role of PcG in human cancer is mostly unknown, but some evidence indicates the involvement of this system in tumorigenesis. Recent studies have demonstrated the importance of certain proteins in several types of human tumor.…”

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confidence: 99%

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

et al. 2006

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In spite of the known function of polycomb group (PcG) genes in stem cell self-renewal, control of cellular proliferation and differentiation, its role in cancer pathogenesis is still poorly understood. We studied the expression by immunohistochemistry of several PcG-maintenance complex proteins (RING1, RNF2, BMI1, MEL18, HPH1 and RYBP) in nontumoral (154 samples) and tumoral (550 samples) human tissues using Tissue Microarrays. For selected genes (BMI1 and RING1) FISH analysis has been also carried out. PcG proteins had a tissue-and cell-type-specific expression pattern. Some of them were highly selectively expressed, such as HPH1, which was detected in germ cells in testis, pituitary and parathyroid glands and Langerhans islets, and RYBP, which was found in placenta, umbilical cord and thyroid gland. By contrast, RING1 was ubiquitously expressed in every normal tissue analyzed. Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts. The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus. These findings imply that upregulation of BMI1 may constitute a malignancy marker in different types of cancer, mainly in lymphoid and endocrine tumors. RING1 was lost in a group of renal-cell carcinomas and testicular germ-cell tumors. Lastly, RYBP is anomalously expressed in Hodgkin's lymphomas and oligodendrogliomas, among others tumors. A significant finding of the study is the identification of unique PcG profiles for some tumors, such as testicular germ-cell tumors, which have high levels of HPH1 expression and loss of RING1 and/ or BMI1; pituitary adenomas, which expressed every PcG protein analyzed; and clear-cell renal-cell carcinoma, which was the only tumor other than testicular germ-cell tumors that did not express RING1.

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Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

et al. 2006

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“…Several recent studies suggest that they also contribute to the development of cancer in humans. 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).…”

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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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“…Overexpression of Bmi-1 causes lymphomas in transgenic mice (Jacobs et al, 1999b) and overexpression of Ring1 leads to cellular transformation and metastatic activity in nude mice (Satijn and Otte, 1999b). Ezh2 has been shown to be upregulated in prostate cancer (Varambally et al, 2002;Rhodes et al, 2003), breast cancer (Perou et al, 2000;Kleer et al, 2003), and in cultured human mantle cell lymphoma (Visser et al, 2001), while an altered Ezh2 expression pattern has been detected in both Hodgkin's disease (Raaphorst et al, 2000) and B-cell non-Hodgkin's lymphomas (van Kemenade et al, 2001). Furthermore, Ezh2 overexpression causes an increase in cellular proliferation (Sellers and Loda, 2002) and promotes anchorage-independent growth and cell invasion in immortalized human mammary epithelial cells lines (Kleer et al, 2003), while inhibition of its expression by antisense oligonucleotides (Fukuyama et al, 2000) and small interfering RNA (siRNA) experiments (Varambally et al, 2002) leads to cell cycle arrest.…”

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confidence: 99%

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

et al. 2004

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The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/ p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/ p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130-HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation.

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The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma

Cited by 213 publications

References 36 publications

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays

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

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

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