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lysine demethylase

Michael Batie, Julianty Frost, Mark Frost, James W Wilson, Pieta Schofield, Sonia Rocha
Oxygen is essential for the life of most multicellular organisms. Cells possess enzymes called molecular dioxygenases that depend on oxygen for activity. A subclass of molecular dioxygenases is the histone demethylase enzymes, which are characterized by the presence of a Jumanji-C (JmjC) domain. Hypoxia can alter chromatin, but whether this is a direct effect on JmjC-histone demethylases or due to other mechanisms is unknown. Here, we report that hypoxia induces a rapid and hypoxia-inducible factor-independent induction of histone methylation in a range of human cultured cells...
March 15, 2019: Science
Barbara Majello, Francesca Gorini, Carmen Daniela Saccà, Stefano Amente
Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes...
March 7, 2019: Cancers
Xudong Shen, Kewei Hu, Guilian Cheng, Liming Xu, Zhengrong Chen, Peng Du, Zhixiang Zhuang
Gastric cancer is one of the top causes of cancer-related death around the world, and poor prognosis of gastric cancer is due to the lack of early detection and effective treatment especially in male. Here, we first revealed the role of histone lysine-specific demethylase 5D (KDM5D) in gastric cancer in male. KDM5D was associated with the metastasis of gastric cancer because of its critical role in the epithelial-mesenchymal transition of gastric cancer cells. Downregulation of KDM5D in gastric cancer cells significantly increase the number of migrated or invaded cells due to the increasing expressions of mesenchymal markers...
March 12, 2019: Journal of Cellular Biochemistry
Fu-Yu Hung, Fang-Fang Chen, Chenlong Li, Chen Chen, Jian-Hao Chen, Yuhai Cui, Keqiang Wu
In Arabidopsis , the circadian rhythm is associated with multiple important biological processes and maintained by multiple interconnected loops that generate robust rhythms. The circadian clock central loop is a negative feedback loop composed of the core circadian clock components. TOC1 ( TIMING OF CAB EXPRESSION 1 ) is highly expressed in the evening and negatively regulates the expression of CCA1 ( CIRCADIAN CLOCK ASSOCIATED 1 )/ LHY ( LATE ELONGATED HYPOCOTYL ). CCA1/LHY also binds to the promoter of TOC1 and represses the TOC1 expression...
2019: Frontiers in Plant Science
Jinfeng Wu, Yasunori Ichihashi, Takamasa Suzuki, Arisa Shibata, Ken Shirasu, Nobutoshi Yamaguchi, Toshiro Ito
After germination, seedlings undergo growth arrest in response to unfavorable conditions, a critical adaptation enabling plants to survive harsh environments. The plant hormone abscisic acid (ABA) plays a key role in this arrest. To arrest growth, ABA-dependent transcription factors change gene expression patterns in a flexible and reversible manner. Although the control of gene expression has important roles in growth arrest, the epigenetic mechanisms in the response to ABA are not fully understood. Here, we show that the histone demethylases JUMONJI-C DOMAIN-CONTAINING PROTEIN30 (JMJ30) and JMJ32 control ABA-mediated growth arrest in Arabidopsis thaliana...
March 12, 2019: Plant, Cell & Environment
Jerzy Dorosz, Line Hyltoft Kristensen, Nanda G Aduri, Osman Mirza, Rikke Lousen, Saskia Bucciarelli, Ved Mehta, Selene Sellés-Baiget, Sara Marie Øie Solbak, Anders Bach, Pablo Mesa, Pablo Alcon Hernandez, Guillermo Montoya, Tam T T N Nguyen, Kasper D Rand, Thomas Boesen, Michael Gajhede
The full length human histone 3 lysine 4 demethylase KDM5B (PLU-1/Jarid1B) has been studied using Hydrogen/Deuterium exchange mass spectrometry, homology modelling, sequence analysis, small angle X-ray scattering and electron microscopy. This first structure on an intact multi-domain Jumonji histone demethylase reveal that the so-called PLU region, in the central region of KDM5B, has a curved α-helical three-dimensional structure, that acts as a rigid linker between the catalytic core and a region comprising four α-helices, a loop comprising the PHD2 domain, two large intrinsically disordered loops and the PHD3 domain in close proximity...
March 11, 2019: Scientific Reports
Marika Mokou, Julie Klein, Manousos Makridakis, Vasiliki Bitsika, Jean-Loup Bascands, Jean Sebastien Saulnier-Blache, William Mullen, Michael Sacherer, Jerome Zoidakis, Burkert Pieske, Harald Mischak, Maria G Roubelakis, Joost P Schanstra, Antonia Vlahou
BACKGROUND: The increased prevalence of cardiovascular disease (CVD) indicates a demand for novel therapeutic approaches. Proteome analysis of vascular tissues from animal models and humans with CVD could lead to the identification of novel druggable targets. METHODS: LC-MS/MS analysis of thoracic aortas from three mouse models of non-diabetic and diabetic (streptozotocin (STZ)-induced) atherosclerosis followed by bioinformatics/pathway analysis was performed. Selected findings were confirmed by proteomics analysis of human vessels from patients with CVD as well as in vitro studies (migration, proliferation, angiogenesis assays) using endothelial (HUVEC) cells...
February 27, 2019: EBioMedicine
Shobhit Chaturvedi, Rajeev Ramanan, Sodiq Waheed, Jon Ainsley, Martin Evison, Jenny Ames, Christopher Schofield, Tatyana Karabencheva-Christova, Christo Christov
The human KDM7 subfamily histone H3 Nɛ-methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates inter-domain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X-linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues...
February 28, 2019: Chemistry: a European Journal
Cristina Mascaró, Alberto Ortega, Elena Carceller, Raquel Ruiz Rodriguez, Filippo Ciceri, Serena Lunardi, Li Yu, Manuel Hilbert, Tamara Maes
Screening of cellular activity for inhibitors of histone lysine modifiers is most frequently performed indirectly by analyzing changes in the total levels of histone marks targeted by lysine methylases /demethylases. However, inhibition of histone lysine modifiers often leads to local rather than total changes in histone marks. Also, since histone modifications can be modulated by more than one cellular enzyme, it is not always clear if changes in histone marks are a direct or indirect consequence of the inhibitor treatment applied...
February 25, 2019: Journal of Biological Chemistry
Ao Li, Dan You, Wenyan Li, Yingjie Cui, Yingzi He, Wen Li, Yan Chen, Xiao Feng, Shan Sun, Renjie Chai, Huawei Li
Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2)...
November 2018: Drug Delivery
Rong Song, Lexun Lin
Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that can modulate osteoblasts and bone mineralization. Periodontal disease (PD) is characterized by gum inflammation, alveolar bone resorption, and tooth loss. In this study, we found that GPNMB is highly expressed in inflamed periodontal tissue through microarray and immunohistochemistry (IHC) assays. The role of GPNMB in the pathogenesis of PD was evaluated with primary human periodontal ligament cells (hPDLCs) treated with lipopolysaccharide (LPS) and a GPNMB-expressing lentivirus (lenti-GP)...
February 22, 2019: Inflammation
Shuai Wang, Zhong-Rui Li, Feng-Zhi Suo, Xiao-Han Yuan, Bin Yu, Hong-Min Liu
The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50  = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B...
April 1, 2019: European Journal of Medicinal Chemistry
Sina Jostes, Daniel Nettersheim, Hubert Schorle
Current treatment regimens for type II testicular germ cell tumours (TGCTs) achieve cure rates of ≥95%; however, 1-5% of TGCTs develop resistance to standard platinum-based chemotherapy. Patients with recurrent TGCT typically receive high-dose chemotherapy, but this treatment results in severe adverse effects and cytotoxicity. Thus, alternative treatment options should be considered to improve patient well-being and quality of life. Epigenetic drugs could be feasible options for TGCT treatment. Several compounds have already been tested in TGCT cell lines and xenograft models with promising results...
February 14, 2019: Nature Reviews. Urology
Priya S Dalvi, Iris F Macheleidt, So-Young Lim, Sonja Meemboor, Marion Muller, Hannah Eischeid-Scholz, Stephan C Schaefer, Reinhard Buettner, Sebastian Klein, Margarete Odenthal
Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma (LUAD), which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the LUAD cell line, PC9 using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell cycle arrest of the tumor cells in the G2/M phase...
February 13, 2019: Molecular Cancer Research: MCR
Cailin Wilson, Adam J Krieg
Epigenetic changes are well-established contributors to cancer progression and normal developmental processes. The reversible modification of histones plays a central role in regulating the nuclear processes of gene transcription, DNA replication, and DNA repair. The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition...
February 12, 2019: Genes
Lu Wang, Ali Shilatifard
Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX, encoded by KDM6A) is a histone demethylase that targets di- and tri-methylated histone H3 lysine 27 (H3K27). UTX function has been linked to homeotic gene expression, embryonic development, and cellular reprogramming. UTX and its protein interactors within the COMPASS family, including the MLL3 and MLL4 lysine methyltransferases, are frequently mutated in multiple human cancers; however, the molecular basis of how these mutations contribute to oncogenesis remains unclear...
February 11, 2019: Cancer Cell
Carolyn M Mitchell, Jonathan J Hirst, Murray D Mitchell, Henry G Murray, Tamas Zakar
Inflammatory genes are expressed increasingly in the fetal membranes at late gestation triggering birth. Here we have examined whether epigenetic histone modifications contribute to the upregulation of proinflammatory genes in the amnion in late pregnancy and at labour. Amnion samples were collected from early pregnancy, at term in the absence of labour and after spontaneous birth. The expression of the labour-associated proinflammatory genes PTGS2, BMP2 and NAMPT was determined by reverse transcription-coupled quantitative real-time PCR (qRT-PCR)...
February 12, 2019: Molecular Human Reproduction
Yuka Miyake, Yukihiro Itoh, Atsushi Hatanaka, Yoshinori Suzuma, Miki Suzuki, Hidehiko Kodama, Yoshinobu Arai, Takayoshi Suzuki
Histone lysine demethylases (KDMs) have drawn much attention as targets of therapeutic agents. KDM5 proteins, which are Fe(II)/α-ketoglutarate-dependent demethylases, are associated with oncogenesis and drug resistance in cancer cells, and KDM5-selective inhibitors are expected to be anticancer drugs. However, few cell-active KDM5 inhibitors have been reported and there is an obvious need to discover more. In this study, we pursued the identification of highly potent and cell-active KDM5-selective inhibitors...
February 4, 2019: Bioorganic & Medicinal Chemistry
Arnaud Augert, Emily Eastwood, Ali H Ibrahim, Nan Wu, Eli Grunblatt, Ryan Basom, Denny Liggitt, Keith D Eaton, Renato Martins, John T Poirier, Charles M Rudin, Francesca Milletti, Wei-Yi Cheng, Fiona Mack, David MacPherson
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis...
February 5, 2019: Science Signaling
Peng Liu, Shuaibin Zhang, Bing Zhou, Xi Luo, Xiaofeng Zhou, Bin Cai, Yin Hua Jin, De Niu, Jinxing Lin, Xiaofeng Cao, Jing Bo Jin
Leaf senescence is governed by a complex regulatory network involving dynamic reprogramming of gene expression. Age-dependent induction of senescence-associated genes (SAGs) is associated with increased level of trimethylation of histone H3 at lysine 4 (H3K4me3), but the regulatory mechanism remains elusive. We found that JMJ16, an Arabidopsis JmjC-domain containing protein, is a specific H3K4 demethylase that negatively regulates leaf senescence through its activity. Genome-wide analysis revealed a widespread coordinated up-regulation of gene expression and hyper-methylation of H3K4me3 at JMJ16 binding genes associated with leaf senescence in the loss-of-function jmj16 mutant compared with the wild type...
February 1, 2019: Plant Cell
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