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Lysine specific demethylase

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https://www.readbyqxmd.com/read/29137219/functional-characterization-of-lysine-specific-demethylase-2-lsd2-kdm1b-in-breast-cancer-progression
#1
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
https://www.readbyqxmd.com/read/29111428/kdm6-and-kdm4-histone-lysine-demethylases-emerge-as-molecular-therapeutic-targets-in-human-acute-myeloid-leukemia
#2
Liberalis Debraj Boila, Shankha Subhra Chatterjee, Debasis Banerjee, Amitava Sengupta
Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy caused by proliferation of immature myeloid cells, which is frequently characterized by perturbations in chromatin modifying enzymes. Emerging evidences indicate that histone demethylases play instructive role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging...
October 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29104258/epigenetic-regulatory-mechanisms-induced-by-resveratrol
#3
REVIEW
Guilherme Felipe Santos Fernandes, Gabriel Dalio Bernardes Silva, Aline Renata Pavan, Diego Eidy Chiba, Chung Man Chin, Jean Leandro Dos Santos
Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1)...
November 1, 2017: Nutrients
https://www.readbyqxmd.com/read/29076964/lysine-methylation-signaling-in-pancreatic-cancer
#4
Gaël S Roth, Alexandre G Casanova, Nathanaël Lemonnier, Nicolas Reynoird
PURPOSE OF REVIEW: Despite better knowledge of its genetic basis, pancreatic cancer is still highly lethal with very few therapeutic options. In this review, we discuss the potential impact of epigenetic therapies, focusing on lysine methylation signaling and its implication in pancreatic cancer. RECENT FINDINGS: Protein lysine methylation, a key mechanism of posttranslational modifications of histone proteins, has emerged as a major cell signaling mechanism regulating physiologic and pathologic processes including cancer...
October 25, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/29069576/novel-combination-of-histone-methylation-modulators-with-therapeutic-synergy-against-acute-myeloid-leukemia-in%C3%A2-vitro-and-in%C3%A2-vivo
#5
Shijun Wen, Jiankang Wang, Panpan Liu, Yiqing Li, Wenhua Lu, Yumin Hu, Jinyun Liu, Zhiyuan He, Peng Huang
Acute myeloid leukemia (AML) is a hematological malignancy with rapid disease progression and often becomes lethal without treatment. Development of effective new therapies is essential to improve the clinical outcome of AML patients. Enhancer of zeste homolog 2 (EZH2) and lysine specific demethylase 1 (LSD1) play important roles in epigenetic regulation and their altered expressions have been observed in cancer. Although EZH2 and LSD1 have opposite histone methylation functions, we found that both enzymes were paradoxically up-regulated in AML cells...
October 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29042477/kdm3a-mediated-demethylation-of-histone-h3-lysine-9-facilitates-the-chromatin-binding-of-neurog2-during-neurogenesis
#6
Hao Lin, Xuechen Zhu, Geng Chen, Lei Song, Li Gao, Aftab A Khand, Ying Chen, Gufa Lin, Qinghua Tao
Neurog2 is a crucial regulator of neuronal fate specification and differentiation in vivo and in vitro However, it remains unclear how Neurog2 transactivates neuronal genes that are silenced by repressive chromatin. Here, we provide evidence that the histone H3 lysine 9 demethylase KDM3A facilitates the Xenopus Neurog2 (formerly known as Xngnr1) chromatin accessibility during neuronal transcription. Loss-of-function analyses reveal that KDM3A is not required for the transition of naive ectoderm to neural progenitor cells but is essential for primary neuron formation...
October 15, 2017: Development
https://www.readbyqxmd.com/read/29037950/discovery-of-tranylcypromine-analogs-with-an-acylhydrazone-substituent-as-lsd1-inactivators-design-synthesis-and-their-biological-evaluation
#7
Kai Sun, Jia-Di Peng, Feng-Zhi Suo, Ting Zhang, Yun-Dong Fu, Yi-Chao Zheng, Hong-Min Liu
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC50 = 91.83 nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29035139/novel-17-bp-deletion-in-kdm1b-gene-is-significantly-associated-with-testis-weight-in-male-piglet
#8
Yang Cui, Tao Hu, Rui Chen, Shuai Yu, Wuzi Dong, Xiaoyan Lv, Chuanying Pan
Lysine-specific demethylase 1B (KDM1B) which plays a crucial role in regulating methylation status at lysine 4 of histone 3 is important for male fertility. The aim of this study was to explore the KDM1B mRNA expression profiles and to identify novel genetic variants of the pig KDM1B gene, as well as to determine the association between these variants and testis measurement traits in male piglets. The KDM1B mRNA expression profiles indicated that this gene widely expressed in all tested organs. In addition, a novel 17-bp deletion (NC_010449...
October 16, 2017: Animal Biotechnology
https://www.readbyqxmd.com/read/29031059/tying-up-tranylcypromine-novel-selective-histone-lysine-specific-demethylase-1-lsd1-inhibitors
#9
Yue-Yang Ji, Sen-Dong Lin, Yu-Jie Wang, Ming-Bo Su, Wei Zhang, Hendra Gunosewoyo, Fan Yang, Jia Li, Jie Tang, Yu-Bo Zhou, Li-Fang Yu
Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28991226/lsd1-promotes-s-phase-entry-and-tumorigenesis-via-chromatin-co-occupation-with-e2f1-and-selective-h3k9-demethylation
#10
Y He, Y Zhao, L Wang, L R Bohrer, Y Pan, L Wang, H Huang
Histone H3 lysine-9 (H3K9) methylation is essential for retinoblastoma protein (RB)-mediated heterochromatin formation, epigenetic silencing of S-phase genes and permanent cell cycle arrest or cellular senescence. Besides as an H3K4 demethylase, lysine-specific demethylase-1 (LSD1) has been shown to promote H3K9 demethylation. However, it is unexplored whether LSD1 has a causal role in regulating cell cycle entry and senescence. Here we demonstrate that genetic depletion or pharmacological inhibition of LSD1 triggers G1 arrest and cellular senescence...
October 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28987602/design-and-synthesis-of-tranylcypromine-derivatives-as-novel-lsd1-hdacs-dual-inhibitors-for-cancer-treatment
#11
Ying-Chao Duan, Yong-Cheng Ma, Wen-Ping Qin, Li-Na Ding, Yi-Chao Zheng, Ying-Li Zhu, Xiao-Yu Zhai, Jing Yang, Chao-Ya Ma, Yuan-Yuan Guan
Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28978483/loss-of-kdm5c-causes-spurious-transcription-and-prevents-the-fine-tuning-of-activity-regulated-enhancers-in-neurons
#12
Marilyn Scandaglia, Jose P Lopez-Atalaya, Alejandro Medrano-Fernandez, Maria T Lopez-Cascales, Beatriz Del Blanco, Michal Lipinski, Eva Benito, Roman Olivares, Shigeki Iwase, Yang Shi, Angel Barco
During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28974232/the-stem-cell-factor-sall4-is-an-essential-transcriptional-regulator-in-mixed-lineage-leukemia-rearranged-leukemogenesis
#13
Lina Yang, Li Liu, Hong Gao, Jaya Pratap Pinnamaneni, Deepthi Sanagasetti, Vivek P Singh, Kai Wang, Megumi Mathison, Qianzi Zhang, Fengju Chen, Qianxing Mo, Todd Rosengart, Jianchang Yang
BACKGROUND: The stem cell factor spalt-like transcription factor 4 (SALL4) plays important roles in normal hematopoiesis and also in leukemogenesis. We previously reported that SALL4 exerts its effect by recruiting important epigenetic factors such as DNA methyltransferases DNMT1 and lysine-specific demethylase 1 (LSD1/KDM1A). Both of these proteins are critically involved in mixed lineage leukemia (MLL)-rearranged (MLL-r) leukemia, which has a very poor clinical prognosis. Recently, SALL4 has been further linked to the functions of MLL and its target gene homeobox A9 (HOXA9)...
October 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28970783/the-histone-h3k27-demethylase-utx-regulates-synaptic-plasticity-and-cognitive-behaviors-in-mice
#14
Gang-Bin Tang, Yu-Qiang Zeng, Pei-Pei Liu, Ting-Wei Mi, Shuang-Feng Zhang, Shang-Kun Dai, Qing-Yuan Tang, Lin Yang, Ya-Jie Xu, Hai-Liang Yan, Hong-Zhen Du, Zhao-Qian Teng, Feng-Quan Zhou, Chang-Mei Liu
Histone demethylase UTX mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish a mechanistic switch to activate large sets of genes. Mutation of Utx has recently been shown to be associated with Kabuki syndrome, a rare congenital anomaly syndrome with dementia. However, its biological function in the brain is largely unknown. Here, we observe that deletion of Utx results in increased anxiety-like behaviors and impaired spatial learning and memory in mice. Loss of Utx in the hippocampus leads to reduced long-term potentiation and amplitude of miniature excitatory postsynaptic current, aberrant dendrite development and defective synapse formation...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28931919/ror%C3%AE-2-requires-lsd1-to-enhance-tumor-progression-in-breast-cancer
#15
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/28927796/development-and-evaluation-of-4-pyrrolidin-3-yl-benzonitrile-derivatives-as-inhibitors-of-lysine-specific-demethylase-1
#16
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...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927255/innate-immune-response-of-bovine-mammary-epithelial-cells-to-mycoplasma-bovis
#17
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/28926430/targeting-histone-methylation-in-cancer
#18
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
#19
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/28905188/novel-inhibitors-of-lysine-k-specific-demethylase-4a-with-anticancer-activity
#20
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...
December 2017: Investigational New Drugs
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