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Elizabeth M Wilson - One of the best experts on this subject based on the ideXlab platform.
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androgen receptor regulation by Histone Methyltransferase suppressor of variegation 3 9 homolog 2 and melanoma antigen a11
Molecular and Cellular Endocrinology, 2017Co-Authors: Emily B Askew, John T. Minges, Amanda B Parris, Elizabeth M WilsonAbstract:Abstract Androgen receptor (AR) transcriptional activity depends on interactions between the AR NH2-terminal region and transcriptional coregulators. A yeast two-hybrid screen of a human testis library using predicted α-helical NH2-terminal fragment AR-(370-420) as bait identified suppressor of variegation 3-9 homolog 2 (SUV39H2) Histone Methyltransferase as an AR interacting protein. SUV39H2 interaction with AR and the AR coregulator, melanoma antigen-A11 (MAGE-A11), was verified in two-hybrid, in vitro glutathione S-transferase affinity matrix and coimmunoprecipitation assays. Fluorescent immunocytochemistry colocalized SUV39H2 and AR in the cytoplasm without androgen, in the nucleus with androgen, and with MAGE-A11 in the nucleus independent of androgen. Chromatin immunoprecipitation using antibodies raised against SUV39H2 demonstrated androgen-dependent recruitment of AR and SUV39H2 to the androgen-responsive upstream enhancer of the prostate-specific antigen gene. SUV39H2 functioned cooperatively with MAGE-A11 to increase androgen-dependent AR transcriptional activity. SUV39H2 Histone Methyltransferase is an AR coactivator that increases androgen-dependent transcriptional activity through interactions with AR and MAGE-A11.
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Androgen receptor regulation by Histone Methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11
Molecular and cellular endocrinology, 2016Co-Authors: Emily B Askew, John T. Minges, Amanda B Parris, Suxia Bai, Elizabeth M WilsonAbstract:Androgen receptor (AR) transcriptional activity depends on interactions between the AR NH2-terminal region and transcriptional coregulators. A yeast two-hybrid screen of a human testis library using predicted α-helical NH2-terminal fragment AR-(370-420) as bait identified suppressor of variegation 3-9 homolog 2 (SUV39H2) Histone Methyltransferase as an AR interacting protein. SUV39H2 interaction with AR and the AR coregulator, melanoma antigen-A11 (MAGE-A11), was verified in two-hybrid, in vitro glutathione S-transferase affinity matrix and coimmunoprecipitation assays. Fluorescent immunocytochemistry colocalized SUV39H2 and AR in the cytoplasm without androgen, in the nucleus with androgen, and with MAGE-A11 in the nucleus independent of androgen. Chromatin immunoprecipitation using antibodies raised against SUV39H2 demonstrated androgen-dependent recruitment of AR and SUV39H2 to the androgen-responsive upstream enhancer of the prostate-specific antigen gene. SUV39H2 functioned cooperatively with MAGE-A11 to increase androgen-dependent AR transcriptional activity. SUV39H2 Histone Methyltransferase is an AR coactivator that increases androgen-dependent transcriptional activity through interactions with AR and MAGE-A11.
Ryuji Hamamoto - One of the best experts on this subject based on the ideXlab platform.
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Histone Methyltransferase smyd2 selective inhibitor lly 507 in combination with poly adp ribose polymerase inhibitor has therapeutic potential against high grade serous ovarian carcinomas
Biochemical and Biophysical Research Communications, 2019Co-Authors: Asako Kukita, Kenbun Sone, Ryuji Hamamoto, Katsutoshi Oda, Syuzo Kaneko, Masaaki Komatsu, Miku Wada, Harunori Honjoh, Yoshiko Kawata, Machiko KojimaAbstract:Dysfunction of Histone methylation is known to be related to cancer progression. The Histone Methyltransferase SMYD2 methylates Histone protein H3 and non-Histone proteins, including poly ADP ribose polymerase 1 (PARP1). There have been reports of SMYD2 overexpression in several types of cancers. However, there are no reports regarding its role in high-grade serous ovarian carcinomas (HGSOCs). Therefore, we investigated the expression profile and conducted functional analysis on SMYD2 in HGSOC cells. In addition, we verified whether SMYD2 inhibition increases the susceptibility of HGSOC cells to PARP inhibitors. We analyzed the expression of Histone Methyltransferase SMYD2 by quantitative real-time polymerase chain reaction and immunohistochemistry using HGSOC clinical tissues (n = 35). We performed functional analyses, including cell proliferation assay, cell cycle analysis, and immunoblotting, after treatment with SMYD2 siRNAs and SMYD2 selective inhibitor LLY-507 in HGSOC cells. We also performed colony-formation assay after combination treatment with LLY-507 and PARP inhibitor olaparib in HGSOC cells. The expression profiles of SMYD2 showed significant overexpression of SMYD2 in HGSOC clinical tissues. The knockdown or inhibition of SMYD2 by siRNAs or LLY-507, respectively, suppressed cell growth by increasing the proportion of apoptotic cells. LLY-507 showed additive effect with olaparib in the colony-formation assay. These findings suggest that LLY-507 can be used alone or in combination with a PARP inhibitor for the treatment of patients with HGSOC.
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abstract 5156 the oncogenic polycomb Histone Methyltransferase ezh2 methylates lysine 120 on Histone h2b and competes ubiquitination in human cancer
Cancer Research, 2014Co-Authors: Ryuji Hamamoto, Yusuke NakamuraAbstract:The Histone Methyltransferase EZH2 is known to be a polycomb protein homologus to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to Histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In this study, we demonstrated that EZH2 has the function to mono-methylated lysine 120 on Histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key post-translational modification of Histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent ChIP-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis. Citation Format: Ryuji Hamamoto, Yusuke Nakamura. The oncogenic polycomb Histone Methyltransferase EZH2 methylates lysine 120 on Histone H2B and competes ubiquitination in human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5156. doi:10.1158/1538-7445.AM2014-5156
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the Histone Methyltransferase smyd2 methylates parp1 and promotes poly adp ribosyl ation activity in cancer cells
Neoplasia, 2014Co-Authors: Lianhua Piao, Yusuke Nakamura, Ryuji Hamamoto, Daechun Kang, Takehiro Suzuki, Akiko Masuda, Naoshi DohmaeAbstract:Poly(ADP-ribose) polymerase-1 (PARP1) catalyzes the poly(ADP-ribosyl)ation of protein acceptors using NAD+ as the substrate is now considered as an important target for development of anticancer therapy. PARP1 is known to be post-translationally modified in various ways including phosphorylation and ubiquitination, but the physiological role of PARP1 methylation is not well understood. Herein we demonstrated that the Histone Methyltransferase SMYD2, which plays critical roles in human carcinogenesis, mono-methylated PARP1. We confirmed lysine 528 to be a target of SMYD2-dependent PARP1 methylation by LC-MS/MS and Edman Degradation analyses. Importantly, methylated PARP1 revealed enhanced poly(ADP-ribose) formation after oxidative stress, and positively regulated the poly(ADP-ribosyl)ation activity of PARP1. Hence, our study unveils a novel mechanism of PARP1 in human cancer through its methylation by SMYD2.
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smyd3 encodes a Histone Methyltransferase involved in the proliferation of cancer cells
Nature Cell Biology, 2004Co-Authors: Ryuji Hamamoto, Fabio Pittella Silva, Yoichi Furukawa, Masashi Morita, Yuko Iimura, Ryuichiro Yagyu, Yusuke NakamuraAbstract:Colorectal and hepatocellular carcinomas are some of the leading causes of cancer deaths worldwide, but the mechanisms that underly these malignancies are not fully understood. Here we report the identification of SMYD3, a gene that is over-expressed in the majority of colorectal carcinomas and hepatocellular carcinomas. Introduction of SMYD3 into NIH3T3 cells enhanced cell growth, whereas genetic knockdown with small-interfering RNAs (siRNAs) in cancer cells resulted in significant growth suppression. SMYD3 formed a complex with RNA polymerase II through an interaction with the RNA helicase HELZ and transactivated a set of genes that included oncogenes, homeobox genes and genes associated with cell-cycle regulation. SMYD3 bound to a motif, 5′-CCCTCC-3′, present in the promoter region of downstream genes such as Nkx2.8. The SET domain of SMYD3 showed Histone H3-lysine 4 (H3-K4)-specific Methyltransferase activity, which was enhanced in the presence of the heat-shock protein HSP90A. Our findings suggest that SMYD3 has Histone Methyltransferase activity and plays an important role in transcriptional regulation as a member of
Axel Imhof - One of the best experts on this subject based on the ideXlab platform.
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activation of rna polymerase i transcription by cockayne syndrome group b protein and Histone Methyltransferase g9a
Molecular Cell, 2007Co-Authors: Xuejun Yuan, Axel Imhof, Weijun Feng, Ingrid Grummt, Yonggang ZhouAbstract:Summary Cockayne syndrome group B (CSB) protein plays a role in both transcription-coupled DNA repair and transcriptional regulation of all three classes of nuclear RNA polymerases. Here we show that a complex consisting of CSB, RNA polymerase I (Pol I), and Histone Methyltransferase G9a is present at active rRNA genes. G9a methylates Histone H3 on lysine 9 (H3K9me2) in the pre-rRNA coding region and facilitates the association of heterochromatin protein 1γ (HP1γ) with rDNA. Both H3K9 methylation and HP1γ association require ongoing transcription. Knockdown of CSB prevents the association of Pol I with rDNA, impairs the interaction of G9a with Pol I, and inhibits pre-rRNA synthesis. Likewise, knockdown of G9a leads to decreased levels of H3K9me2 in the transcribed region and downregulation of pre-rRNA synthesis. The results reveal the mechanism underlying CSB-mediated activation of rDNA transcription and link G9a-dependent H3K9 methylation to Pol I transcription elongation through chromatin.
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identification of a specific inhibitor of the Histone Methyltransferase su var 3 9
Nature Chemical Biology, 2005Co-Authors: Dorothea Greiner, Tiziana Bonaldi, Ragnhild Eskeland, Ernst Roemer, Axel ImhofAbstract:Histone methylation plays a key role in establishing and maintaining stable gene expression patterns during cellular differentiation and embryonic development. Here, we report the characterization of the fungal metabolite chaetocin as the first inhibitor of a lysine-specific Histone Methyltransferase. Chaetocin is specific for the Methyltransferase SU(VAR)3-9 both in vitro and in vivo and may therefore be used to study heterochromatin-mediated gene repression.
Onur Boyman - One of the best experts on this subject based on the ideXlab platform.
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the Histone Methyltransferase ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy
Cell Reports, 2017Co-Authors: Daniel Zingg, Natalia Arenasramirez, Dilara Sahin, Rodney A Rosalia, Ana T Antunes, Jessica Haeusel, Lukas Sommer, Onur BoymanAbstract:Summary Immunotherapy and particularly immune checkpoint inhibitors have resulted in remarkable clinical responses in patients with immunogenic tumors, although most cancers develop resistance to immunotherapy. The molecular mechanisms of tumor resistance to immunotherapy remain poorly understood. We now show that induction of the Histone Methyltransferase Ezh2 controls several tumor cell-intrinsic and extrinsic resistance mechanisms. Notably, T cell infiltration selectively correlated with high EZH2-PRC2 complex activity in human skin cutaneous melanoma. During anti-CTLA-4 or IL-2 immunotherapy in mice, intratumoral tumor necrosis factor-α (TNF-α) production and T cell accumulation resulted in increased Ezh2 expression in melanoma cells, which in turn silenced their own immunogenicity and antigen presentation. Ezh2 inactivation reversed this resistance and synergized with anti-CTLA-4 and IL-2 immunotherapy to suppress melanoma growth. These anti-tumor effects depended on intratumorally accumulating interferon-γ (IFN-γ)-producing PD-1 low CD8 + T cells and PD-L1 downregulation on melanoma cells. Hence, Ezh2 serves as a molecular switch controlling melanoma escape during T cell-targeting immunotherapies.
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the Histone Methyltransferase ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy
Cell Reports, 2017Co-Authors: Daniel Zingg, Natalia Arenasramirez, Dilara Sahin, Rodney A Rosalia, Ana T Antunes, Jessica Haeusel, Lukas Sommer, Onur BoymanAbstract:Summary Immunotherapy and particularly immune checkpoint inhibitors have resulted in remarkable clinical responses in patients with immunogenic tumors, although most cancers develop resistance to immunotherapy. The molecular mechanisms of tumor resistance to immunotherapy remain poorly understood. We now show that induction of the Histone Methyltransferase Ezh2 controls several tumor cell-intrinsic and extrinsic resistance mechanisms. Notably, T cell infiltration selectively correlated with high EZH2-PRC2 complex activity in human skin cutaneous melanoma. During anti-CTLA-4 or IL-2 immunotherapy in mice, intratumoral tumor necrosis factor-α (TNF-α) production and T cell accumulation resulted in increased Ezh2 expression in melanoma cells, which in turn silenced their own immunogenicity and antigen presentation. Ezh2 inactivation reversed this resistance and synergized with anti-CTLA-4 and IL-2 immunotherapy to suppress melanoma growth. These anti-tumor effects depended on intratumorally accumulating interferon-γ (IFN-γ)-producing PD-1 low CD8 + T cells and PD-L1 downregulation on melanoma cells. Hence, Ezh2 serves as a molecular switch controlling melanoma escape during T cell-targeting immunotherapies.
Yuan Yuan - One of the best experts on this subject based on the ideXlab platform.
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a small molecule probe of the Histone Methyltransferase g9a induces cellular senescence in pancreatic adenocarcinoma
ACS Chemical Biology, 2012Co-Authors: Yuan Yuan, Qiu Wang, Joshiawa Paulk, Stefan Kubicek, Melissa M Kemp, Drew J AdamsAbstract:Post-translational modifications of Histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin Histone Methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on Histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel Histone Methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in ...
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a small molecule probe of the Histone Methyltransferase g9a induces cellular senescence in pancreatic adenocarcinoma
ACS Chemical Biology, 2012Co-Authors: Yuan Yuan, Qiu Wang, Joshiawa Paulk, Stefan Kubicek, Melissa M Kemp, Drew J Adams, Alykhan F ShamjiAbstract:Post-translational modifications of Histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin Histone Methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on Histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel Histone Methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology.