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Lysine specific demethylase

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https://www.readbyqxmd.com/read/29331452/design-synthesis-and-evaluation-of-%C3%AE-turn-mimetics-as-lsd1-selective-inhibitors
#1
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity...
January 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29311580/lsd1-activation-promotes-inducible-emt-programs-and-modulates-the-tumour-microenvironment-in-breast-cancer
#2
T Boulding, R D McCuaig, A Tan, K Hardy, F Wu, J Dunn, M Kalimutho, C R Sutton, J K Forwood, A G Bert, G J Goodall, L Malik, D Yip, J E Dahlstrom, A Zafar, K K Khanna, S Rao
Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29298815/genome-wide-characterisation-of-dna-methylation-in-an-invasive-lepidopteran-pest-the-cotton-bollworm-helicoverpa-armigera
#3
Christopher M Jones, Ka S Lim, Jason W Chapman, Chris Bass
The genes and genomes of insect pests are shaped by the wide array of selective forces encountered in their environments. While the molecular adaptations that evolve are beginning to be understood at the genomic and transcriptomic level they have been less well characterised at an epigenetic level. Here, we present a genome-wide map of DNA methylation, at single-nucleotide resolution for the cotton bollworm moth, Helicoverpa armigera; a globally invasive pest of agriculture. We show that methylation is almost identical in the larvae and adults of H...
January 3, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29286083/kdm3a-inhibition-attenuates-high-concentration-insulin%C3%A2-induced-vascular-smooth-muscle-cell-injury-by-suppressing-mapk-nf%C3%A2-%C3%AE%C2%BAb-pathways
#4
Bo-Fang Zhang, Hong Jiang, Jing Chen, Xin Guo, Qi Hu, Shuo Yang
Previous studies have indicated that lysine (K)‑specific demethylase 3A (KDM3A) is associated with diverse diabetes‑associated cardiovascular complications in response to high glucose levels. However, the effects of KDM3A on the pathological progression of cardiovascular injuries in response to high insulin levels remain unknown. The present study aimed to explore whether KDM3A knockdown may attenuate high insulin‑induced vascular smooth muscle cell (VSMC) dysfunction, and to further investigate the underlying mechanisms...
December 29, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29282356/long-non-coding-rna-dleu1-predicts-poor-prognosis-of-gastric-cancer-and-contributes-to-cell-proliferation-by-epigenetically-suppressing-klf2
#5
Xiaobin Li, Zongze Li, Ziwen Liu, Jianchun Xiao, Shuting Yu, Yimin Song
Currently, accumulating documents have paid great attention to the critical role of long non-coding RNAs. The long non-coding RNAs DLEU1 has been demonstrated to be dysregulated in many solid tumors and hematological malignancies. However, the detailed descriptions about its potential roles and molecular mechanism in gastric cancer (GC) are still blurry. As for our research, it was found out that DLEU1 was observably intensified in GC tissues and cell lines. And highly expressed DLEU1 was relevant to tumor size, advanced stage of pathology and lymph node metastasis in GC patients...
December 27, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/29281014/systematic-genetic-interaction-studies-identify-histone-demethylase-utx-as-potential-target-for-ameliorating-huntington-s-disease
#6
Wan Song, Nóra Zsindely, Anikó Faragó, J Lawrence Marsh, László Bodai
Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins...
December 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29274582/bioactivity-evaluation-of-natural-product-%C3%AE-mangostin-as-a-novel-xanthone-based-lysine-specific-demethylase-1-inhibitor-to-against-tumor-metastasis
#7
Chao Han, Zhongrui Li, Jiqin Hou, Zhen Wang, Dingqiao Xu, Guimin Xue, Lingyi Kong
Lysine-specific demethylase 1 (LSD1), which has been reported to be overexpressed in several human cancers, has recently emerged as an attractive therapeutic target for treating cancer. To date, almost all the developed LSD1 inhibitors are chemo-synthesized molecules, while α-mangostin is first characterized as xanthone-based natural inhibitor in the current study with IC50 values of 2.81 ± 0.44 μM. Bioactivity study and docking analysis indicated that α-mangostin could inhibit MDA-MB-231 cells migration and evasion through inhibit intracellular LSD1 activity...
December 8, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29247860/structure-activity-studies-on-n-substituted-tranylcypromine-derivatives-lead-to-selective-inhibitors-of-lysine-specific-demethylase-1-lsd1-and-potent-inducers-of-leukemic-cell-differentiation
#8
Johannes Schulz-Fincke, Mirjam Hau, Jessica Barth, Dina Robaa, Dominica Willmann, Andreas Kürner, Julian Haas, Gabriele Greve, Tinka Haydn, Simone Fulda, Michael Lübbert, Steffen Lüdeke, Tobias Berg, Wolfgang Sippl, Roland Schüle, Manfred Jung
FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase-inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N-substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals...
December 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29247011/histone-demethylase-activity-of-utx-is-essential-for-viability-and-regulation-of%C3%A2-hox-gene-expression-in%C3%A2-drosophila
#9
Ömer Copur, Jürg Müller
The trimethylation of histone H3 at lysine 27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) is essential for repression of Polycomb target genes. The role of enzymatic demethylation of H3K27me3 by the KDM6-family demethylases Utx, Uty and JmjD3 is however less clear. Studies in both mice and worms led to the proposal that KDM6 proteins but not their H3K27me3 demethylase activity is critical for normal development. Here, we investigated the requirement of the demethylase activity of the single KDM6 family member Utx in Drosophila We generated Drosophila expressing full-length but catalytic inactive Utx protein and found that these mutants show the same phenotypes like animals lacking Utx protein...
December 15, 2017: Genetics
https://www.readbyqxmd.com/read/29239273/bioluminescent-high-throughput-succinate-detection-method-for-monitoring-the-activity-of-jmjc-histone-demethylases-and-fe-ii-2-oxoglutarate-dependent-dioxygenases
#10
Juliano Alves, Gediminas Vidugiris, Said A Goueli, Hicham Zegzouti
The modification of a diverse array of substrates by Fe(II)/2-oxoglutarate-dependent dioxygenases is central to the modulation of distinct biological processes such as epigenetics, hypoxic signaling, and DNA/RNA repair. Of these, JumonjiC domain-containing histone lysine demethylases (JMJCs) and prolyl hydroxylases are potential drug targets due to their relevance to human diseases. Thus, assays to interrogate this enzyme superfamily are needed to identify selective and potent inhibitors as leads for drug development and that could also be useful research tools...
December 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29233856/structure-of-the-arabidopsis-jmj14-h3k4me3-complex-provides-insight-into-the-substrate-specificity-of-kdm5-subfamily-histone-demethylases
#11
Zhenlin Yang, Qi Qiu, Wei Chen, Bei Jia, Xiaomei Chen, Hongmiao Hu, Kaixuan He, Xian Deng, Sisi Li, W Andy Tao, XiaoFeng Cao, Jiamu Du
In chromatin, histone methylation affects the epigenetic regulation of multiple processes in animals and plants and is modulated by the activities of histone methyltransferases and histone demethylases. The jumonji domain-containing histone demethylases have diverse functions and can be classified into several subfamilies. In humans, the jumonji domain-containing Lysine (K)-Specific Demethylase 5/Jumonji and ARID Domain Protein (KDM5/JARID) subfamily demethylases are specific for histone 3 lysine 4 trimethylation (H3K4me3) and are important drug targets for cancer treatment...
December 12, 2017: Plant Cell
https://www.readbyqxmd.com/read/29226080/fad-influx-enhances-neuronal-differentiation-of-human-neural-stem-cells-by-facilitating-nuclear-localization-of-lsd1
#12
Kazumi Hirano, Masakazu Namihira
Flavin adenine dinucleotide (FAD), synthesized from riboflavin, is redox cofactor in energy production and plays an important role in cell survival. More recently, riboflavin deficiency has been linked to developmental disorders, but its role in stem cell differentiation remains unclear. Here, we show that FAD treatment, using DMSO as a solvent, enabled an increase in the amount of intracellular FAD and promoted neuronal differentiation of human neural stem cells (NSCs) derived not only from fetal brain, but also from induced pluripotent stem cells...
December 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/29225781/lsd1-a-double-edged-sword-confers-dynamic-chromatin-regulation-but-commonly-promotes-aberrant-cell-growth
#13
REVIEW
Meghan M Kozub, Ryan M Carr, Gwen L Lomberk, Martin E Fernandez-Zapico
Histone-modifying enzymes play a critical role in chromatin remodeling and are essential for influencing several genome processes such as gene expression and DNA repair, replication, and recombination. The discovery of lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, dramatically revolutionized research in the field of epigenetics. LSD1 plays a pivotal role in a wide range of biological operations, including development, cellular differentiation, embryonic pluripotency, and disease (for example, cancer)...
2017: F1000Research
https://www.readbyqxmd.com/read/29220567/the-structural-basis-of-the-histone-demethylase-kdm6b-histone-3-lysine-27-specificity
#14
Sarah Elizabeth Jones, Lars Olsen, Michael Gajhede
KDM subfamily 6 enzymes KDM6A and KDM6B specifically catalyse demethylation of di-/tri-methylated lysine on Histone 3 lysine 27 (H3K27me3/2) and play an important role in repression of developmental genes. Despite identical amino acid sequence in the immediate surroundings of H3K9me3/2 (ARKS) the enzymes do not catalyse demethylation of this general marker of repression. In order to address this question for KDM6B we used computational methods to identify H3(17-33) derived peptides with improved binding affinity, that would enable co-crystallization with the catalytic core of human KDM6B (ccKDM6B)...
December 8, 2017: Biochemistry
https://www.readbyqxmd.com/read/29212818/the-histone-demethylase-kdm5a-is-required-for-the-repression-of-astrocytogenesis-and-regulated-by-the-translational-machinery-in-neural-progenitor-cells
#15
Sun-Young Kong, Woosuk Kim, Ha-Rim Lee, Hyun-Jung Kim
Histone demethylases are known to play important roles in the determination of the fate of stem cells and in cancer progression. In this study, we show that the lysine 4 of histone H3 (H3K4), lysine-specific demethylase 5A (KDM5A) is essential for the repression of astrocyte differentiation in neural progenitor cells (NPCs), and its expression is regulated by translational machinery. Knockdown of KDM5A in NPCs increased astrocytogenesis, and conversely, KDM5A overexpression reduced the transcriptional activity of the Gfap promoter...
December 6, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29198865/histone-h3-peptides-incorporating-modified-lysine-residues-as-lysine-specific-demethylase-1-inhibitors
#16
Taeko Kakizawa, Yosuke Ota, Yukihiro Itoh, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position...
November 23, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29161028/exploring-the-active-centre-of-lsd1-corest-complex-by-molecular-dynamics-simulation-utilizing-its-co-crystallized-cofactor-tetrahydrofolate-as-a-probe
#17
Waleed A A Zalloum, Hiba M Zalloum
Epigenetic targeting of cancer is a recent era to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and uses tetrahydrofolate as a cofactor to accept CH2 from the demethylation process...
November 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29156705/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#18
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29152043/lysine-specific-demethylase-1-lsd1-inhibitors-as-potential-treatment-for-different-types-of-cancers
#19
EDITORIAL
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29137219/functional-characterization-of-lysine-specific-demethylase-2-lsd2-kdm1b-in-breast-cancer-progression
#20
Lin Chen, Shauna N Vasilatos, Ye Qin, Tiffany A Katz, Chunyu Cao, Hao Wu, Nilgun Tasdemir, Kevin M Levine, Steffi Oesterreich, Nancy E Davidson, Yi Huang
Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line...
October 10, 2017: Oncotarget
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