The Experts below are selected from a list of 4314 Experts worldwide ranked by ideXlab platform
Celina G Kleer - One of the best experts on this subject based on the ideXlab platform.
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repression of e cadherin by the Polycomb Group Protein ezh2 in cancer
Oncogene, 2008Co-Authors: Qi Cao, Ram Shankar Mani, Celina G Kleer, Saravana M. Dhanasekaran, Jung H Kim, Scott A Tomlins, Rohit Mehra, Bharathi Laxman, Xuhong Cao, Sooryanarayana VaramballyAbstract:Enhancer of zeste homolog 2 (EZH2) is a critical component of the Polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.
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identification of ezh2 as a molecular marker for a precancerous state in morphologically normal breast tissues
Cancer Research, 2006Co-Authors: Lei Ding, Christine A Erdmann, Arul M Chinnaiyan, Sofia D Merajver, Celina G KleerAbstract:The discovery of molecular markers to detect the precancerous state would have profound implications in the prevention of breast cancer. We report that the expression of the Polycomb Group Protein EZH2 increases in histologically normal breast epithelium with higher risk of developing cancer. We identify EZH2 as a potential marker for detecting preneoplastic lesions of the breast in vivo and as a possible target for preventative intervention. (Cancer Res 2006; 66(8): 4095-9)
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the Polycomb Group Protein ezh2 impairs dna repair in breast epithelial cells
Cancer Research, 2006Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:1064 The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreases the expression of five RAD51 paralog Proteins involved in homologous recombination repair (HR) of DNA double strand breaks (DSB): RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2 and XRCC3, but did not affect the levels of DMC1 a gene which only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific down-regulation of RAD51-like Proteins and impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way to explore blockade of EZH2 overexpression as a novel approach for prevention and treatment of breast cancer.
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The Polycomb Group Protein EZH2 impairs DNA repair in breast epithelial cells.
Neoplasia (New York N.Y.), 2005Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog Proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like Proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.
Sooryanarayana Varambally - One of the best experts on this subject based on the ideXlab platform.
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repression of e cadherin by the Polycomb Group Protein ezh2 in cancer
Oncogene, 2008Co-Authors: Qi Cao, Ram Shankar Mani, Celina G Kleer, Saravana M. Dhanasekaran, Jung H Kim, Scott A Tomlins, Rohit Mehra, Bharathi Laxman, Xuhong Cao, Sooryanarayana VaramballyAbstract:Enhancer of zeste homolog 2 (EZH2) is a critical component of the Polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.
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the Polycomb Group Protein ezh2 impairs dna repair in breast epithelial cells
Cancer Research, 2006Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:1064 The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreases the expression of five RAD51 paralog Proteins involved in homologous recombination repair (HR) of DNA double strand breaks (DSB): RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2 and XRCC3, but did not affect the levels of DMC1 a gene which only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific down-regulation of RAD51-like Proteins and impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way to explore blockade of EZH2 overexpression as a novel approach for prevention and treatment of breast cancer.
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The Polycomb Group Protein EZH2 impairs DNA repair in breast epithelial cells.
Neoplasia (New York N.Y.), 2005Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog Proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like Proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.
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ezh2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Celina G Klee, Arie P Otte, Sooryanarayana Varambally, Qi Cao, Debashis Ghosh, Ronglai She, Ichiro Ota, Sco A Tomlins, Richard George Antonius Bernardus Sewal, Daniel F HayesAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive prostate cancer. Here we investigate the functional role of EZH2 in cancer cell invasion and breast cancer progression. EZH2 transcript and Protein were consistently elevated in invasive breast carcinoma compared with normal breast epithelia. Tissue microarray analysis, which included 917 samples from 280 patients, demonstrated that EZH2 Protein levels were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity. This study provides compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.
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The Polycomb Group Protein EZH2 is involved in progression of prostate cancer
Nature, 2002Co-Authors: Sooryanarayana Varambally, Saravana M. Dhanasekaran, Ming Zhou, Terrence R. Barrette, Chandan Kumar-sinha, Martin G. Sanda, Debashis Ghosh, Kenneth J. Pienta, Richard George Antonius Bernardus Sewalt, Arie P OtteAbstract:Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the Polycomb Group Protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 Protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 Protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
Qi Cao - One of the best experts on this subject based on the ideXlab platform.
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repression of e cadherin by the Polycomb Group Protein ezh2 in cancer
Oncogene, 2008Co-Authors: Qi Cao, Ram Shankar Mani, Celina G Kleer, Saravana M. Dhanasekaran, Jung H Kim, Scott A Tomlins, Rohit Mehra, Bharathi Laxman, Xuhong Cao, Sooryanarayana VaramballyAbstract:Enhancer of zeste homolog 2 (EZH2) is a critical component of the Polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.
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the Polycomb Group Protein ezh2 impairs dna repair in breast epithelial cells
Cancer Research, 2006Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:1064 The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreases the expression of five RAD51 paralog Proteins involved in homologous recombination repair (HR) of DNA double strand breaks (DSB): RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2 and XRCC3, but did not affect the levels of DMC1 a gene which only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific down-regulation of RAD51-like Proteins and impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way to explore blockade of EZH2 overexpression as a novel approach for prevention and treatment of breast cancer.
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The Polycomb Group Protein EZH2 impairs DNA repair in breast epithelial cells.
Neoplasia (New York N.Y.), 2005Co-Authors: Michael G. Zeidler, Arul M Chinnaiyan, Sofia D Merajver, Sooryanarayana Varambally, Qi Cao, David O. Ferguson, Celina G KleerAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog Proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like Proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.
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ezh2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Celina G Klee, Arie P Otte, Sooryanarayana Varambally, Qi Cao, Debashis Ghosh, Ronglai She, Ichiro Ota, Sco A Tomlins, Richard George Antonius Bernardus Sewal, Daniel F HayesAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive prostate cancer. Here we investigate the functional role of EZH2 in cancer cell invasion and breast cancer progression. EZH2 transcript and Protein were consistently elevated in invasive breast carcinoma compared with normal breast epithelia. Tissue microarray analysis, which included 917 samples from 280 patients, demonstrated that EZH2 Protein levels were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity. This study provides compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.
Haruhiko Koseki - One of the best experts on this subject based on the ideXlab platform.
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the Polycomb Group Protein ring1 regulates dorsoventral patterning of the mouse telencephalon
Nature Communications, 2020Co-Authors: Hikaru Eto, Haruhiko Koseki, Yusuke Kishi, Nayuta Yakushijikaminatsui, Hiroki Sugishita, Shun Utsunomiya, Yukiko GotohAbstract:Dorsal-ventral patterning of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminence. While Bone morphogenetic Protein (BMP), Wnt, and Sonic hedgehog (Shh) signaling are known to determine regional identity along the dorsoventral axis, how the region-specific expression of these morphogens is established remains unclear. Here we show that the Polycomb Group (PcG) Protein Ring1 contributes to the ventralization of the mouse telencephalon. Deletion of Ring1b or both Ring1a and Ring1b in neuroepithelial cells induces ectopic expression of dorsal genes, including those for BMP and Wnt ligands, as well as attenuated expression of the gene for Shh, a key morphogen for ventralization, in the ventral telencephalon. We observe PcG Protein-mediated trimethylation of histone 3 at lysine-27 and binding of Ring1B at BMP and Wnt ligand genes specifically in the ventral region. Furthermore, forced activation of BMP or Wnt signaling represses Shh expression. Our results thus indicate that PcG Proteins suppress BMP and Wnt signaling in a region-specific manner and thereby allow proper Shh expression and development of the ventral telencephalon.
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the Polycomb Group Protein ring1 regulates dorsoventral patterning of the mouse telencephalon
bioRxiv, 2019Co-Authors: Hikaru Eto, Haruhiko Koseki, Yusuke Kishi, Yukiko GotohAbstract:Summary Patterning of the dorsal-ventral (D-V) axis of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminences. Morphogenetic signaling by bone morphogenetic Protein (BMP), Wnt, Sonic hedgehog (Shh), and fibroblast growth factor (FGF) pathways determines regional identity along this axis. It has remained unclear, however, how region-specific expression patterns of these morphogens along the D-V axis are established, especially at the level of epigenetic (chromatin) regulation. Here we show that epigenetic regulation by Ring1, an essential Polycomb Group (PcG) Protein, plays a key role in formation of ventral identity in the mouse telencephalon. Deletion of the Ring1b or both Ring1a and Ring1b genes in neuroepithelial cells of the mouse embryo attenuated expression of the gene for Shh, a key morphogen for induction of ventral identity, and induced misexpression of dorsal marker genes including those for BMP and Wnt ligands in the ventral telencephalon. PcG Protein–mediated trimethylation of histone H3 on lysine-27 (H3K27me3) was also apparent at BMP and Wnt ligand genes in wild-type embryos. Importantly, forced activation of Wnt or BMP signaling repressed the expression of Shh in organotypic and dissociated cultures of the early-stage telencephalon. Our results thus indicate that epigenetic regulation by PcG Proteins—and, in particular, that by Ring1— confers a permissive state for the induction of Shh expression through suppression of BMP and Wnt signaling pathways, which in turn allows the development of ventral identity in the telencephalon.
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loss of ezh2 promotes a midbrain to forebrain identity switch by direct gene derepression and wnt dependent regulation
BMC Biology, 2015Co-Authors: Martina Zemke, Haruhiko Koseki, Kalina Draganova, Annika Klug, Anne Scholer, Luis Zurkirchen, Phil F Cheng, Tomas Valenta, Dirk Schubeler, Konrad BaslerAbstract:Background Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development. This process involves epigenetic control mechanisms, such as those mediated by the Polycomb Group Protein Ezh2, which catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression.
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CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis
Cancer cell, 2011Co-Authors: Jiaying Tan, Morgan Jones, Haruhiko Koseki, Manabu Nakayama, Andrew G. Muntean, Ivan Maillard, Jay L HessAbstract:Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion Proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group Protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.
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The Polycomb Group Protein SUZ12 regulates histone H3 lysine 9 methylation and HP1α distribution
Chromosome Research, 2007Co-Authors: Cecile C De La Cruz, Antonis Kirmizis, Haruhiko Koseki, Matthew D. Simon, Kyo-ichi Isono, Barbara PanningAbstract:Regulation of histone methylation is critical for proper gene expression and chromosome function. Suppressor of Zeste 12 (SUZ12) is a requisite member of the EED/EZH2 histone methyltransferase complexes, and is required for full activity of these complexes in vitro . In mammals and flies, SUZ12/Su(z)12 is necessary for trimethylation of histone H3 on lysine 27 (H3K27me3) on facultative heterochromatin. However, Su(z)12 is unique among Polycomb Group Proteins in that Su(z)12 mutant flies exhibit gross defects in position effect variegation, suggesting a role for Su(z)12 in constitutive heterochromatin formation. We investigated the role of Suz12 in constitutive heterochromatin and discovered that Suz12 is required for histone H3 lysine 9 tri-methylation (H3K9me3) in differentiated but not undifferentiated mouse embryonic stem cells. Knockdown of SUZ12 in human cells caused a reduction in H3K27me3 and H3K9me3, and altered the distribution of HP1α. In contrast, EZH2 knockdown caused loss of H3K27me3 but not H3K9me3, indicating that SUZ12 regulates H3-K9 methylation in an EZH2-independent fashion. This work uncovers a role for SUZ12 in H3-K9 methylation.
Arie P Otte - One of the best experts on this subject based on the ideXlab platform.
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the murine Polycomb Group Protein eed is required for global histone h3 lysine 27 methylation
Current Biology, 2005Co-Authors: Nathan D. Montgomery, Della Yee, Andrew Chen, Sundeep Kalantry, Stormy J Chamberlain, Arie P Otte, Terry MagnusonAbstract:Summary PcG Proteins mediate heritable transcriptional silencing by generating and recognizing covalent histone modifications. One conserved PcG complex, PRC2, is composed of several Proteins including the histone methyltransferase (HMTase) Ezh2, the WD-repeat Protein Eed, and the Zn-finger Protein Suz12. Ezh2 methylates histone H3 on lysine 27 (H3K27) [1–4], which serves as an epigenetic mark mediating silencing. H3K27 can be mono-, di-, or trimethylated (1mH3K27, 2mH3K27, and 3mH3K27, respectively) [5]. Hence, either PRC2 must be regulated so as to add one methyl Group to certain nucleosomes but two or three to others, or distinct complexes must be responsible for 1m-, 2m-, and 3mH3K27. Consistent with the latter possibility, 2mH3K27 and 3mH3K27, but not 1mH3K27, are absent in Suz12 −/− embryos, which lack both Suz12 and Ezh2 Protein [6]. Mammalian Proteins required for 1mH3K27 have not been identified. Here, we demonstrate that unlike Suz12 and Ezh2, Eed is required not only for 2m- and 3mH3K27 but also global 1mH3K27. These results provide a functionally important distinction between PRC2 complex components and implicate Eed in PRC2-independent histone methylation.
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gene repression by Polycomb Group Protein complexes a distinct complex for every occasion
Current Opinion in Genetics & Development, 2003Co-Authors: Arie P Otte, Ted H J KwaksAbstract:Polycomb Group (PcG) Proteins play important roles in maintaining the repressed transcriptional state of genes. PcG Proteins operate as part of Polycomb repressive complexes (PRCs). 'Core' PRCs have been purified that contain only a limited number of PcG Proteins. In addition, many gene regulatory Proteins have been identified to interact with PcG Proteins. However, it remains subject to discussion whether these interactions are transient or whether the regulatory Proteins are real components of PRCs. It has also become clear that the compositions of 'core' PRCs differ amongst cell types and that extensive changes in compositions occur during the embryonic development of cells. Because of these dynamic changes, we argue that speaking of a definitive core PRC can be misleading.
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ezh2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Celina G Klee, Arie P Otte, Sooryanarayana Varambally, Qi Cao, Debashis Ghosh, Ronglai She, Ichiro Ota, Sco A Tomlins, Richard George Antonius Bernardus Sewal, Daniel F HayesAbstract:The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive prostate cancer. Here we investigate the functional role of EZH2 in cancer cell invasion and breast cancer progression. EZH2 transcript and Protein were consistently elevated in invasive breast carcinoma compared with normal breast epithelia. Tissue microarray analysis, which included 917 samples from 280 patients, demonstrated that EZH2 Protein levels were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity. This study provides compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.
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The Polycomb Group Protein EZH2 is involved in progression of prostate cancer
Nature, 2002Co-Authors: Sooryanarayana Varambally, Saravana M. Dhanasekaran, Ming Zhou, Terrence R. Barrette, Chandan Kumar-sinha, Martin G. Sanda, Debashis Ghosh, Kenneth J. Pienta, Richard George Antonius Bernardus Sewalt, Arie P OtteAbstract:Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the Polycomb Group Protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 Protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 Protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
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identification and characterization of interactions between the vertebrate Polycomb Group Protein bmi1 and human homologs of polyhomeotic
Molecular and Cellular Biology, 1997Co-Authors: M J Gunster, Maarten Van Lohuizen, David P E Satijn, Karien M Hamer, Jan Den L Blaauwen, Mark J Alkema, R Van Driel, D R H De Bruijn, Arie P OtteAbstract:In Drosophila melanogaster, the Polycomb-Group (PcG) genes have been identified as repressors of gene expression. They are part of a cellular memory system that is responsible for the stable transmission of gene activity to progeny cells. PcG Proteins form a large multimeric, chromatin-associated Protein complex, but the identity of its components is largely unknown. Here, we identify two human Proteins, HPH1 and HPH2, that are associated with the vertebrate PcG Protein BMI1. HPH1 and HPH2 coimmunoprecipitate and cofractionate with each other and with BMI1. They also colocalize with BMI1 in interphase nuclei of U-2 OS human osteosarcoma and SW480 human colorectal adenocarcinoma cells. HPH1 and HPH2 have little sequence homology with each other, except in two highly conserved domains, designated homology domains I and II. They share these homology domains I and II with the Drosophila PcG Protein Polyhomeotic (Ph), and we, therefore, have named the novel Proteins HPH1 and HPH2. HPH1, HPH2, and BMI1 show distinct, although overlapping expression patterns in different tissues and cell lines. Two-hybrid analysis shows that homology domain II of HPH1 interacts with both homology domains I and II of HPH2. In contrast, homology domain I of HPH1 interacts only with homology domain II of HPH2, but not with homology domain I of HPH2. Furthermore, BMI1 does not interact with the individual homology domains. Instead, both intact homology domains I and II need to be present for interactions with BMI1. These data demonstrate the involvement of homology domains I and II in Protein-Protein interactions and indicate that HPH1 and HPH2 are able to heterodimerize.