The Experts below are selected from a list of 6396 Experts worldwide ranked by ideXlab platform
Jihye Seong - One of the best experts on this subject based on the ideXlab platform.
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in silico probing and biological evaluation of setdb1 eset targeted novel compounds that reduce tri methylated Histone h3k9 h3k9me3 level
Journal of Computer-aided Molecular Design, 2017Co-Authors: Ashwini M. Londhe, Seo Yun Jung, Jihye Seong, Ambily Nath Indu Viswanath, Yu Jin Hwang, Insun ParkAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington’s disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico–in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.
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In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated Histone H3K9 (H3K9me3) level
Journal of Computer-Aided Molecular Design, 2017Co-Authors: Insun Park, Ashwini M. Londhe, Seo Yun Jung, Kyoung Mi Sim, Sun Joon Min, Ambily Nath Indu Viswanath, Yu Jin Hwang, Tae-hun Kim, Ji Eun Lee, Jihye SeongAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.
Insun Park - One of the best experts on this subject based on the ideXlab platform.
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in silico probing and biological evaluation of setdb1 eset targeted novel compounds that reduce tri methylated Histone h3k9 h3k9me3 level
Journal of Computer-aided Molecular Design, 2017Co-Authors: Ashwini M. Londhe, Seo Yun Jung, Jihye Seong, Ambily Nath Indu Viswanath, Yu Jin Hwang, Insun ParkAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington’s disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico–in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.
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In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated Histone H3K9 (H3K9me3) level
Journal of Computer-Aided Molecular Design, 2017Co-Authors: Insun Park, Ashwini M. Londhe, Seo Yun Jung, Kyoung Mi Sim, Sun Joon Min, Ambily Nath Indu Viswanath, Yu Jin Hwang, Tae-hun Kim, Ji Eun Lee, Jihye SeongAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.
Rik Derynck - One of the best experts on this subject based on the ideXlab platform.
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smad3 mediated recruitment of the Methyltransferase setdb1 eset controls snail1 expression and epithelial mesenchymal transition
EMBO Reports, 2018Co-Authors: Dan Du, Yoko Katsuno, Dominique S Meyer, Erine H Budi, Sihan Chen, Rosemary J Akhurst, Hartmut Koeppen, Hongjun Wang, Rik DerynckAbstract:During epithelial-mesenchymal transition (EMT), reprogramming of gene expression is accompanied by Histone modifications. Whether EMT-promoting signaling directs functional changes in Histone methylation has not been established. We show here that the Histone Lysine Methyltransferase SETDB1 represses EMT and that, during TGF-β-induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. SETDB1 also controls stem cell generation, cancer cell motility, invasion, metastatic dissemination, as well as sensitivity to certain cancer drugs. These functions may explain the correlation of breast cancer patient survival with SETDB1 expression. At the molecular level, TGF-β induces SETDB1 recruitment by Smad3, to repress Smad3/4-activated transcription of SNAI1, encoding the EMT "master" transcription factor SNAIL1. Suppression of SNAIL1-mediated gene reprogramming by SETDB1 occurs through H3K9 methylation at the SNAI1 gene that represses its H3K9 acetylation imposed by activated Smad3/4 complexes. SETDB1 therefore defines a TGF-β-regulated balance between Histone methylation and acetylation that controls EMT.
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Smad3‐mediated recruitment of the Methyltransferase SETDB1/ESET controls Snail1 expression and epithelial–mesenchymal transition
EMBO Reports, 2017Co-Authors: Dan Du, Yoko Katsuno, Dominique S Meyer, Erine H Budi, Rosemary J Akhurst, Si‐han Chen, Hartmut Koeppen, Hongjun Wang, Rik DerynckAbstract:During epithelial-mesenchymal transition (EMT), reprogramming of gene expression is accompanied by Histone modifications. Whether EMT-promoting signaling directs functional changes in Histone methylation has not been established. We show here that the Histone Lysine Methyltransferase SETDB1 represses EMT and that, during TGF-β-induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. SETDB1 also controls stem cell generation, cancer cell motility, invasion, metastatic dissemination, as well as sensitivity to certain cancer drugs. These functions may explain the correlation of breast cancer patient survival with SETDB1 expression. At the molecular level, TGF-β induces SETDB1 recruitment by Smad3, to repress Smad3/4-activated transcription of SNAI1, encoding the EMT "master" transcription factor SNAIL1. Suppression of SNAIL1-mediated gene reprogramming by SETDB1 occurs through H3K9 methylation at the SNAI1 gene that represses its H3K9 acetylation imposed by activated Smad3/4 complexes. SETDB1 therefore defines a TGF-β-regulated balance between Histone methylation and acetylation that controls EMT.
Ryuji Hamamoto - One of the best experts on this subject based on the ideXlab platform.
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Automethylation of SUV39H2, an oncogenic Histone Lysine Methyltransferase, regulates its binding affinity to substrate proteins
Oncotarget, 2016Co-Authors: Lianhua Piao, Takehiro Suzuki, Makoto Nakakido, Ryuji HamamotoAbstract:// Lianhua Piao 1 , Makoto Nakakido 1 , Takehiro Suzuki 2 , Naoshi Dohmae 2 , Yusuke Nakamura 1 , Ryuji Hamamoto 1, 3 1 Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA 2 Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan 3 Division of Molecular Modification and Cancer Biology, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan Correspondence to: Ryuji Hamamoto, e-mail: ryujihamamoto@gmail.com Keywords: SUV39H2, oncogene, automethylation, SET domain Received: November 12, 2015 Accepted: February 25, 2016 Published: March 14, 2016 ABSTRACT We previously reported that the Histone Lysine Methyltransferase SUV39H2, which is overexpressed in various types of human cancer, plays a critical role in the DNA repair after double strand breakage, and possesses oncogenic activity. Although its biological significance in tumorigenesis has been elucidated, the regulatory mechanism of SUV39H2 activity through post-translational modification is not well known. In this study, we demonstrate in vitro and in vivo automethylation of SUV39H2 at Lysine 392. Automethylation of SUV39H2 led to impairment of its binding affinity to substrate proteins such as Histone H3 and LSD1. Furthermore, we observed that hyper-automethylated SUV39H2 reduced methylation activities to substrates through affecting the binding affinity to substrate proteins. Our finding unveils a novel autoregulatory mechanism of SUV39H2 through Lysine automethylation.
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SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells
Oncotarget, 2015Co-Authors: Lianhua Piao, Yusuke Nakamura, Naoshi Dohmae, Takehiro Suzuki, Ryuji HamamotoAbstract:// Lianhua Piao 1 , Takehiro Suzuki 2 , Naoshi Dohmae 2 , Yusuke Nakamura 1 and Ryuji Hamamoto 1 1 Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA 2 Biomolecular Characterizaion Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan Correspondence to: Ryuji Hamamoto, email: // Keywords : SUV39H2, carcinogenesis, LSD1, non-Histone protein methylation Received : May 02, 2015 Accepted : June 26, 2015 Published : July 03, 2015 Abstract LSD1 is a Histone Lysine demethylase, which is highly expressed in multiple types of human cancer. Although its roles in transcriptional regulation have been well-studied, functional regulation of LSD1 by post-translational modifications still remains unknown. Here, we demonstrate that the Histone Lysine Methyltransferase SUV39H2 trimethylated LSD1 on Lysine 322. Knockdown of SUV39H2 resulted in a decrease of LSD1 protein even though the mRNA levels were unchanged. SUV39H2-induced LSD1 methylation suppresses LSD1 polyubiquitination and subsequent degradation. In addition, we also observed indirect effect of SUV39H2 overexpression on LSD1-target genes. Our results reveal the regulatory mechanism of LSD1 protein through its Lysine methylation by SUV39H2 in human cancer cells.
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abstract 4819 wolf hirschhorn syndrome candidate 1 a Histone Lysine Methyltransferase is involved in human carcinogenesis
Cancer Research, 2011Co-Authors: Ryuji Hamamoto, Hyun-soo Cho, Gouji Toyokawa, Masanori Yoshimatsu, Yusuke NakamuraAbstract:A number of Histone Methyltransferases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human diseases like cancer are not well understood. Here, we demonstrate that Wolf-Hirschhorn syndrome candidate 1 (WHSC1) plays an important role in human carcinogenesis. Transcriptional levels of this gene are significantly elevated in various types of cancer including bladder and lung cancers. Immunohistochemical analysis using a number of clinical tissues confirmed significant up-regulation of WHSC1 expression in bladder and lung cancer cells at the protein level. Treatment of cancer cell lines with small interfering RNAs targeting WHSC1 significantly knocked down its expression and resulted in the suppression of proliferation. Moreover, knockdown of WHSC1 decreased the cell population of cancer cells at S phase and increased that at G2/M phase through the regulation of genes involved in the Wnt signaling pathway. Furthermore, we found WHSC1 to be interacted with some proteins related to the Wnt pathway including β-catenin. As expression levels of WHSC1 are significantly low in normal tissues, it may be feasible to develop the inhibitors targeting these enzymes as anti-tumor agents which have a minimal risk of adverse reaction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4819. doi:10.1158/1538-7445.AM2011-4819
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abstract 3019 demethylation of rb regulator mypt1 by Histone demethylase lsd1 promotes cell cycle progression in cancer cells
Cancer Research, 2011Co-Authors: Hyun-soo Cho, Yusuke Nakamura, Ryuji HamamotoAbstract:Histone demethylase LSD1 (also known as KDM1 and AOF2) is active in various cancer cells, but its biological significance in human carcinogenesis is unexplored. In this study, we explored hypothesized interactions between LSD1 and MYPT1, a known regulator of RB1 phosphorylation. We found that MYPT1 was methylated in vitro and in vivo by Histone Lysine Methyltransferase SETD7 and demethylated by LSD1, identifying Lys 442 of MYPT1 as a target for methylation/demethylation by these enzymes. LSD1 silencing increased MYPT1 protein levels, decreasing the steady-state level of phosphorylated RB1 (Ser 807/811) and reducing E2F activity. MYPT1 methylation status influenced the affinity of MYPT1 for the ubiquitin-proteasome pathway of protein turnover. MYPT1 was unstable in murine cells deficient in SETD7, supporting the concept that MYPT1 protein stability is physiologically regulated by methylation status. LSD1 overexpression could activate RB1 phosphorylation by inducing a destabilization of MYPT1 protein. Taken together, our results comprise a novel cell cycle regulatory mechanism mediated by methylation/demethylation dynamics, and they reveal the significance of LSD1 overexpression in human carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3019. doi:10.1158/1538-7445.AM2011-3019
Ashwini M. Londhe - One of the best experts on this subject based on the ideXlab platform.
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in silico probing and biological evaluation of setdb1 eset targeted novel compounds that reduce tri methylated Histone h3k9 h3k9me3 level
Journal of Computer-aided Molecular Design, 2017Co-Authors: Ashwini M. Londhe, Seo Yun Jung, Jihye Seong, Ambily Nath Indu Viswanath, Yu Jin Hwang, Insun ParkAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington’s disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico–in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.
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In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated Histone H3K9 (H3K9me3) level
Journal of Computer-Aided Molecular Design, 2017Co-Authors: Insun Park, Ashwini M. Londhe, Seo Yun Jung, Kyoung Mi Sim, Sun Joon Min, Ambily Nath Indu Viswanath, Yu Jin Hwang, Tae-hun Kim, Ji Eun Lee, Jihye SeongAbstract:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a Histone Lysine Methyltransferase (HKMT) and it preferentially tri-methylates Lysine 9 of Histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.