The Experts below are selected from a list of 20112 Experts worldwide ranked by ideXlab platform
Masoud Vedadi - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship studies for enhancer of zeste homologue 2 EZH2 and enhancer of zeste homologue 1 ezh1 inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Xiaobao Yang, Kyle D. Konze, Jamel Meslamani, Peter Brown, Mingming Zhou, C H Arrowsmith, Umit H Kaniskan, Masoud VedadiAbstract:EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure–activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.
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selective inhibition of EZH2 and ezh1 enzymatic activity by a small molecule suppresses mll rearranged leukemia
Blood, 2014Co-Authors: Trevor Parton, Kyle D. Konze, Masoud Vedadi, Samantha G Pattenden, David F Allison, Ling Cai, Shira Rockowitz, Shichong Liu, Ying Liu, Stephen V FryeAbstract:Enhancer of zeste homolog 2 (EZH2) and related EZH1 control gene expression and promote tumorigenesis via methylating histone H3 at lysine 27 (H3K27). These methyltransferases are ideal therapeutic targets due to their frequent hyperactive mutations and overexpression found in cancer, including hematopoietic malignancies. Here, we characterized a set of small molecules that allow pharmacologic manipulation of EZH2 and EZH1, which include UNC1999, a selective inhibitor of both enzymes, and UNC2400, an inactive analog compound useful for assessment of off-target effect. UNC1999 suppresses global H3K27 trimethylation/dimethylation (H3K27me3/2) and inhibits growth of mixed lineage leukemia (MLL)-rearranged leukemia cells. UNC1999-induced transcriptome alterations overlap those following knockdown of embryonic ectoderm development, a common cofactor of EZH2 and EZH1, demonstrating UNC1999's on-target inhibition. Mechanistically, UNC1999 preferentially affects distal regulatory elements such as enhancers, leading to derepression of polycomb targets including Cdkn2a. Gene derepression correlates with a decrease in H3K27me3 and concurrent gain in H3K27 acetylation. UNC2400 does not induce such effects. Oral administration of UNC1999 prolongs survival of a well-defined murine leukemia model bearing MLL-AF9. Collectively, our study provides the detailed profiling for a set of chemicals to manipulate EZH2 and EZH1 and establishes specific enzymatic inhibition of polycomb repressive complex 2 (PRC2)-EZH2 and PRC2-EZH1 by small-molecule compounds as a novel therapeutics for MLL-rearranged leukemia.
Mamoru Harada - One of the best experts on this subject based on the ideXlab platform.
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New peptides of the polycomb group protein enhancer of zeste homolog 2 with the potential to induce cancer-reactive cytotoxic T lymphocytes in human leukocyte antigen-A2+ prostate cancer patients
Oncology reports, 2007Co-Authors: Yukoh Itoh, Yoshihiro Komohara, Nobukazu Komatsu, Takafumi Minami, Koujiro Saito, Masanori Noguchi, Kyogo Itoh, Mamoru HaradaAbstract:The polycomb group protein enhancer of zeste homolog 2 (EZH2) is linked to aggressive prostate cancer and could be an appropriate target in specific immunotherapy. In this study, we attempted to identify EZH2-derived peptides that have the potential to generate cancer-reactive cytotoxic T lymphocytes (CTLs) in human leukocyte antigen (HLA)-A2 + prostate cancer patients. Twelve EZH2-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). As a result, five EZH2 peptides recognized by IgG (EZH2 120-128, EZH2 165-174, EZH2 569-577, EZH2 665-674, and EZH2 699-708) were frequently detected in the plasma of prostate cancer patients. Among them, the EZH2 120-128 and EZH2 165-174 peptides effectively induced HLA-A2-restricted and cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and HLA-A2-restricted CD8 + T cells. These results indicate that these EZH2 120-128 and EZH2 165-174 peptides could be promising candidates in peptide-based immunotherapy for HLA-A2 + prostate cancer patients.
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Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)-derived peptides immunogenic in HLA-A24+ prostate cancer patients.
The Prostate, 2004Co-Authors: Rika Ogata, Masanori Noguchi, Kyogo Itoh, Satoko Matsueda, Akihisa Yao, Mamoru HaradaAbstract:Background Antigens overexpressed in metastatic prostate cancer are appropriate targets in anti-cancer immunotherapy, and one candidate is the polycomb group protein enhancer of zeste homolog 2 (EZH2). Methods Eleven EZH2-derived peptides were prepared based on the HLA-A24 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). Results IgGs reactive to three EZH2 peptides (EZH2-243 to -252, EZH2-291 to -299, and EZH2-735 to -;742) were detected in the plasma of almost half of prostate cancer patients. Among them, the EZH2-291 to -299 and EZH2-735 to -742 peptides effectively induced HLA-A24-restricted and prostate cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and CD8+ T cells. Conclusions These EZH2-291 to -299 and EZH2-735 to -742 peptides could be promising candidates for peptide-based immunotherapy for HLA-A24+ prostate cancer patients with metastases. © 2004 Wiley-Liss, Inc.
Woo Kyun Bae - One of the best experts on this subject based on the ideXlab platform.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by ezh1 and EZH2
PLOS Genetics, 2020Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and EZH2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of EZH2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/EZH2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/EZH2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/EZH2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by ezh1 and EZH2
bioRxiv, 2019Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Summary Background Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous catalytic subunits Ezh1 and EZH2, at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver. Results We used Ezh1-knockout mice with a hepatocyte-specific knockout of EZH2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/EZH2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were induced in Ezh1/EZH2-deficient livers, which may contribute to the increased sensitivity of these mice to hepatotoxin-induced liver pathology. Conclusions Ezh1/EZH2-catalyzed H3K27-trimethyation is thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of the sex-bias in liver disease susceptibility.
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The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.
Molecular carcinogenesis, 2014Co-Authors: Woo Kyun Bae, Kyung Hyun Yoo, Ji Shin Lee, Young Ho Kim, Ik-joo Chung, Min Ho Park, Jung Han Yoon, Priscilla A. Furth, Lothar HennighausenAbstract:Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and EZH2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
Lothar Hennighausen - One of the best experts on this subject based on the ideXlab platform.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by ezh1 and EZH2
PLOS Genetics, 2020Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and EZH2. Here, we used Ezh1-knockout mice with a hepatocyte-specific knockout of EZH2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/EZH2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/EZH2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/EZH2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.
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sex biased genetic programs in liver metabolism and liver fibrosis are controlled by ezh1 and EZH2
bioRxiv, 2019Co-Authors: Dana Laucorona, Woo Kyun Bae, Lothar Hennighausen, David J WaxmanAbstract:Summary Background Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous catalytic subunits Ezh1 and EZH2, at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver. Results We used Ezh1-knockout mice with a hepatocyte-specific knockout of EZH2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/EZH2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were induced in Ezh1/EZH2-deficient livers, which may contribute to the increased sensitivity of these mice to hepatotoxin-induced liver pathology. Conclusions Ezh1/EZH2-catalyzed H3K27-trimethyation is thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of the sex-bias in liver disease susceptibility.
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The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.
Molecular carcinogenesis, 2014Co-Authors: Woo Kyun Bae, Kyung Hyun Yoo, Ji Shin Lee, Young Ho Kim, Ik-joo Chung, Min Ho Park, Jung Han Yoon, Priscilla A. Furth, Lothar HennighausenAbstract:Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and EZH2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
Xiaobao Yang - One of the best experts on this subject based on the ideXlab platform.
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Discovery of a first-in-class EZH2 selective degrader.
Nature chemical biology, 2019Co-Authors: Elias E. Stratikopoulos, Xiaobao Yang, Kwang-su Park, Jieli Wei, Tiphaine Martin, Megan C. Schwarz, Violetta V. Leshchenko, Alexander Rialdi, Brandon DaleAbstract:The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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structure activity relationship studies for enhancer of zeste homologue 2 EZH2 and enhancer of zeste homologue 1 ezh1 inhibitors
Journal of Medicinal Chemistry, 2016Co-Authors: Xiaobao Yang, Kyle D. Konze, Jamel Meslamani, Peter Brown, Mingming Zhou, C H Arrowsmith, Umit H Kaniskan, Masoud VedadiAbstract:EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure–activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity.
