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https://www.readbyqxmd.com/read/28931919/ror%C3%AE-2-requires-lsd1-to-enhance-tumor-progression-in-breast-cancer
#1
Kyeongkyu Kim, Ji Min Lee, Young Suk Yu, Hyunkyung Kim, Hye Jin Nam, Hyeong-Gon Moon, Dong-Young Noh, Keun Il Kim, Sungsoon Fang, Sung Hee Baek
Retinoic acid-related orphan receptor α (RORα) regulates diverse physiological processes, including inflammatory responses, lipid metabolism, circadian rhythm, and cancer biology. RORα has four different isoforms which have distinct N-terminal domains but share identical DNA binding domain and ligand binding domain in human. However, lack of specific antibody against each RORα isoform makes biochemical studies on each RORα isoform remain unclear. Here, we generate RORα2-specific antibody and characterize the role of RORα2 in promoting tumor progression in breast cancer...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28928876/heterochromatin-reduction-correlates-with-the-increase-of-the-kdm4b-and-kdm6a-demethylases-and-the-expression-of-pericentromeric-dna-during-the-acquisition-of-a-transformed-phenotype
#2
Cinthya Gurrion, Maritere Uriostegui, Mario Zurita
Cancer cells have alterations in chromatin organization, mostly a reduction in heterochromatin. How this process occurs during transformation and if it participates in the maintenance of a cancerous phenotype is not well understood. Here, using a transformation-inducible cell line, we analyzed the changes that occur in heterochromatin during transformation to a cancerous phenotype. After transformation, there is a reduction in heterochromatin bodies and a nuclear reorganization of HP1α. These occurrences correlate with reductions in H3K9me3 and H3K27me3 levels and with some of the enzymes that introduce these modifications...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28927796/development-and-evaluation-of-4-pyrrolidin-3-yl-benzonitrile-derivatives-as-inhibitors-of-lysine-specific-demethylase-1
#3
Daniel P Mould, Ulf Bremberg, Allan M Jordan, Matthis Geitmann, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Donald J Ogilvie
As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86...
August 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927255/innate-immune-response-of-bovine-mammary-epithelial-cells-to-mycoplasma-bovis
#4
Satoshi Gondaira, Hidetoshi Higuchi, Hidetomo Iwano, Koji Nishi, Takanori Nebu, Keiichi Nakajima, Hajime Nagahata
Mycoplasma species are contagious bacteria and Mycoplasma bovis mastitis is a serious productivity problem on dairy farms. Bovine mammary epithelial cells (bMEC) play an important role in the elimination of pathogens, but the effect of M. bovis on bMEC has not been fully clarified. To better understand the immune response against intramammary infection by M. bovis, we used microarray analysis to examine and profile mRNA expression in bMEC after stimulation with M. bovis. We also compared the effects of M. bovis, Staphylococcus aureus and Escherichia coli on immune-related mRNA expression in bMEC...
September 20, 2017: Journal of Veterinary Science
https://www.readbyqxmd.com/read/28927230/multi-azole-resistant-strains-of-cryptococcus-neoformans-var-grubii-isolated-from-a-flz-resistant-strain-by-culturing-in-medium-containing-voriconazole
#5
Rui Kano, Miki Okubo, Atsuhiko Hasegawa, Hiroshi Kamata
A Cryptococcus neoformans var. grubii strain, NUBS14020, was the first fluconazole (FLZ)-resistant strain isolated from a feline cryptococcosis. Subsequent work demonstrated that multi-azole-resistant strains are readily isolated from FLZ-resistant strains by culturing in medium containing voriconazole (VRZ). The resulting clones were assessed for mutation and expression of known target genes, including the loci encoding lanosterol 14-α demethylase (ERG11), an ATP-binding cassette (ABC) transporter (AFR1), or a multidrug efflux pump (MEP); mutation and/or overexpression of these genes is known to be associated with azole resistance...
September 11, 2017: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
https://www.readbyqxmd.com/read/28926430/targeting-histone-methylation-in-cancer
#6
Michael T McCabe, Helai P Mohammad, Olena Barbash, Ryan G Kruger
Most, if not all, human cancers exhibit altered epigenetic signatures that promote aberrant gene expression that contributes to cellular transformation. Historically, attempts to pharmacologically intervene in this process have focused on DNA methylation and histone acetylation. More recently, genome-wide studies have identified histone and chromatin regulators as one of the most frequently dysregulated functional classes in a wide range of cancer types. These findings have provided numerous potential therapeutic targets including many that affect histone methylation...
September 2017: Cancer Journal
https://www.readbyqxmd.com/read/28925393/lysine-specific-demethylase-kdm3a-regulates-ovarian-cancer-stemness-and-chemoresistance
#7
S Ramadoss, S Sen, I Ramachandran, S Roy, G Chaudhuri, R Farias-Eisner
This corrects the article DOI: 10.1038/onc.2016.320.
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28923956/arabidopsis-m-6-a-demethylase-activity-modulates-viral-infection-of-a-plant-virus-and-the-m-6-a-abundance-in-its-genomic-rnas
#8
Mireya Martínez-Pérez, Frederic Aparicio, Maria Pilar López-Gresa, Jose María Bellés, Jesus A Sánchez-Navarro, Vicente Pallás
N(6)-methyladenosine (m(6)A) is an internal, reversible nucleotide modification that constitutes an important regulatory mechanism in RNA biology. Unlike mammals and yeast, no component of the m(6)A cellular machinery has been described in plants at present. m(6)A has been identified in the genomic RNAs of diverse mammalian viruses and, additionally, viral infection was found to be modulated by the abundance of m(6)A in viral RNAs. Here we show that the Arabidopsis thaliana protein atALKBH9B (At2g17970) is a demethylase that removes m(6)A from single-stranded RNA molecules in vitro...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923852/tet-mediated-sequestration-of-mir-26-drives-ezh2-expression-and-gastric-carcinogenesis
#9
Min Deng, Ruixin Zhang, Zhengxi He, Qinwei Qiu, Xihong Lu, Jiang Yin, Hao Liu, Xiaoting Jia, Zhimin He
DNA demethylases of the TET family function as tumor suppressors in various human cancers but their pathogenic contributions and mechanisms of action in gastric carcinogenesis and progression remain unclear. Here we report that TET is transcriptionally upregulated in gastric cancer (GC) where it correlates with poor prognosis. Mechanistic investigations revealed that TET facilitated gastric carcinogenesis through a non-coding function of the 3'UTR which interacted with miR-26. This interaction resulted in sequestration of miR-26 from its target EZH2, which released the suppression on EZH2, and thereby leaded to EZH2 overexpression in gastric cancer...
September 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28905188/novel-inhibitors-of-lysine-k-specific-demethylase-4a-with-anticancer-activity
#10
Hyo Jeong Lee, Bo-Kyoung Kim, Kyoung Bin Yoon, Yong-Chul Kim, Sun-Young Han
Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56 μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking...
September 14, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28903624/repair-of-calvarial-bone-defect-using-jarid1a-knockdown-bone-mesenchymal-stem-cells-in-rats
#11
Yuan Deng, Tao Guo, Jipeng Li, Li Guo, Ping Gu, Xianqun Fan
Histone methylation is regarded as an important epigenetic event during stem cell differentiation. Jumonji AT-rich interactive domain 1A (Jarid1a) is a histone demethylase that specifically catalyzes demethylation of dimethyl or trimethyl histone H3K4me3, which is normally associated with transcriptionally active genes. Runt-related transcription factor 2 (Runx2) has been identified as a key transcription factor in the early stage of osteogenesis. A better understanding of this epigenetic mechanism that governs osteogenic differentiation of bone mesenchymal stem cells (BMSCs) can provide new insights into BMSCs based bone tissue engineering...
September 13, 2017: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/28899795/microrna-137-and-its-downstream-target-lsd1-inversely-regulate-anesthetics-induced-neurotoxicity-in-dorsal-root-ganglion-neurons
#12
Lingyang Chen, Xiaodan Wang, Wenguang Huang, Tingting Ying, Minjuan Chen, Jianbin Cao, Mingcang Wang
PURPOSE: Anesthetic reagents, such as bupivacaine (Bv), induce significant neurotoxicity in dorsal root ganglion neurons (DRGNs). In this study, we investigated the expression, function and cross-association of microRNA-137-3p (miR-137-3p) and lysine (K)-specific demethylase 1A (LSD1) in a murine model of Bv-induced neural injury in DRGNs. METHODS: Murine DRGNs were culture in vitro and treated with Bv. QPCR was used to evaluate miR-137-3p expression in Bv-injured DRGNs...
September 9, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28895234/runx2-induction-during-differentiation-of-wharton-s-jelly-mesenchymal-stem-cells-to-osteoblasts-is-regulated-by-jarid1b-histone-demethylase
#13
Francisco Bustos, Hugo Sepúlveda, Catalina P Prieto, Margarita Carrasco, Lorena Díaz, José Palma, José Lattus, Martín Montecino, Verónica Palma
Novel bone regeneration approaches aim to obtain immature osteoblasts from somatic stem cells. Umbilical cord Wharton's jelly mesenchymal stem cells (WJ-MSC) are an ideal source for cell therapy. Hence, the study of mechanisms involved in WJ-MSC osteoblastic differentiation is crucial to exploit their developmental capacity. Here, we have assessed epigenetic control of the RUNX2 osteogenic master regulator gene in WJ-MSC. We present evidence indicating that modulation of RUNX2 expression through preventing JARID1B histone demethylase activity is relevant to enhance WJ-MSC osteoblastic potential...
September 12, 2017: Stem Cells
https://www.readbyqxmd.com/read/28894455/dna-demethylase-regulated-genes-show-methylation-independent-spatiotemporal-expression-patterns
#14
Ulrike Schumann, Joanne Lee, Kemal Kazan, Michael Ayliffe, Ming-Bo Wang
Recent research has indicated that a subset of defense-related genes is downregulated in the Arabidopsis DNA demethylase triple mutant rdd (ros1 dml2 dml3) resulting in increased susceptibility to the fungal pathogen Fusarium oxysporum. In rdd plants these downregulated genes contain hypermethylated transposable element sequences (TE) in their promoters, suggesting that this methylation represses gene expression in the mutant and that these sequences are actively demethylated in wild-type plants to maintain gene expression...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28894299/dhea-inhibits-acute-microglia-mediated-inflammation-through-activation-of-the-trka-akt1-2-creb-jmjd3-pathway
#15
V I Alexaki, G Fodelianaki, A Neuwirth, C Mund, A Kourgiantaki, E Ieronimaki, K Lyroni, M Troullinaki, C Fujii, W Kanczkowski, A Ziogas, M Peitzsch, S Grossklaus, B Sönnichsen, A Gravanis, S R Bornstein, I Charalampopoulos, C Tsatsanis, T Chavakis
Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein...
September 12, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28894274/kdm4a-regulates-hif-1-levels-through-h3k9me3
#16
Grzegorz Dobrynin, Tom E McAllister, Katarzyna B Leszczynska, Shaliny Ramachandran, Adam J Krieg, Akane Kawamura, Ester M Hammond
Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28892629/development-of-4-cyanophenyl-glycine-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#17
Daniel P Mould, Cristina Alli, Ulf Bremberg, Sharon Cartic, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Fabrice Turlais, Donald Ogilvie
Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1)...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892104/synergistic-anti-aml-effects-of-the-lsd1-inhibitor-t-3775440-and-the-nedd8-activating-enzyme-inhibitor-pevonedistat-via-transdifferentiation-and-dna-rereplication
#18
Y Ishikawa, K Nakayama, M Morimoto, A Mizutani, A Nakayama, K Toyoshima, A Hayashi, S Takagi, R Dairiki, H Miyashita, S Matsumoto, K Gamo, T Nomura, K Nakamura
Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation...
September 11, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28890349/molecular-hydrogen-modulates-gene-expression-via-histone-modification-and-induces-the-mitochondrial-unfolded-protein-response
#19
Sayaka Sobue, Chisato Inoue, Fumiko Hori, Shanlou Qiao, Takashi Murate, Masatoshi Ichihara
Molecular hydrogen (H2) is a biologically active gas that is used medically to ameliorate various systemic pathological conditions. H2 also regulates gene expression involved in intracellular signaling and metabolic pathways. However, it is unclear whether H2 affects gene expression directly or through indirect effects as a consequence of health improvement. Therefore, we attempted to identify genes that exhibit similar changes in expression in response to H2 by employing DNA microarrays and gene set enrichment analysis to analyze RNA from liver and lung of rats and mice with or without dietary stress...
September 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28889393/epigenetic-treatment-options-in-urothelial-carcinoma
#20
Maria Pinkerneil, Michèle J Hoffmann, Günter Niegisch
Mutations, dysregulation, and dysbalance of epigenetic regulators are especially frequent in urothelial carcinoma (UC) compared to other malignancies. Accordingly, targeting epigenetic regulators may provide a window of opportunity particularly in anticancer therapy of UC. In general, these epigenetic regulators comprise DNA methyltransferases and DNA demethylases (for DNA methylation), histone methyltransferases, and histone demethylases (for histone methylation) as well as acetyl transferases and histone deacetylases (for histone and non-histone acetylation)...
2018: Methods in Molecular Biology
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