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https://www.readbyqxmd.com/read/27711046/histone-lysine-demethylases-of-jmjd2-or-kdm4-family-are-important-epigenetic-regulators-in-reward-circuitry-in-the-etiopathology-of-depression
#1
Salil Saurav Pathak, Swati Maitra, Sumana Chakravarty, Arvind Kumar
Major depressive disorder (MDD) is debilitating mental illness and is one of the leading contributors to global burden of disease, but unfortunately newer and better drugs are not forthcoming. The reason is lack of complete understanding of molecular mechanisms underlying the development of this disorder. Recent research shows dysregulation in epigenetic regulatory mechanisms, particularly the transcriptionally repressive di- and tri-methylation of histone 3 lysine 9 (H3K9me2/me3) in nucleus accumbens (NAc), a critical region of the reward pathway involved in the development of anhedonia, the hallmark of depression...
October 6, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27664837/insights-into-the-epigenetic-mechanisms-involving-histone-lysine-methylation-and-demethylation-in-ischemia-induced-damage-and-repair-has-therapeutic-implication
#2
Sumana Chakravarty, Priya Jhelum, Unis Ahmad Bhat, Wenson D Rajan, Swati Maitra, Salil S Pathak, Anant B Patel, Arvind Kumar
Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. Therapeutic interventions to minimize ischemia-induced neural damage are limited due to poor understanding of molecular mechanisms mediating complex pathophysiology in stroke. Recently, epigenetic mechanisms mostly histone lysine (K) acetylation and deacetylation have been implicated in ischemic brain damage and have expanded the dimensions of potential therapeutic intervention to the systemic/local administration of histone deacetylase inhibitors...
September 21, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27630312/strong-kdm4b-and-kdm4d-expression-associates-with-radioresistance-and-aggressive-phenotype-in-classical-hodgkin-lymphoma
#3
Hamid Bur, Kirsi-Maria Haapasaari, Taina Turpeenniemi-Hujanen, Outi Kuittinen, Päivi Auvinen, Katja Marin, Ylermi Soini, Peeter Karihtala
BACKGROUND: Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors. MATERIALS AND METHODS: We assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma...
September 2016: Anticancer Research
https://www.readbyqxmd.com/read/27372758/purification-biochemical-analysis-and-structure-determination-of-jmjc-lysine-demethylases
#4
S Krishnan, R C Trievel
Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the site- and state-specific demethylation of lysine residues in histone and nonhistone protein substrates. These enzymes have been implicated in diverse genomic processes, including epigenetic gene regulation, DNA damage response, DNA replication, and regulation of heterochromatin structure. In addition, a number of JmjC KDMs contribute to the incidence of numerous cancers, rendering them targets for the development of novel chemotherapeutic drugs. Using the JMJD2 KDM subfamily as representative examples, this chapter outlines strategies for purifying highly active, recombinant JmjC KDMs lacking inhibitory transition metal ions, characterizing kinetic parameters of these enzymes using a coupled fluorescent assay, and determining crystal structures of the enzymes in complex with methylated histone peptides...
2016: Methods in Enzymology
https://www.readbyqxmd.com/read/27266524/continual-removal-of-h3k9-promoter-methylation-by-jmjd2-demethylases-is-vital-for-esc-self-renewal-and-early-development
#5
Marianne Terndrup Pedersen, Susanne Marije Kooistra, Aliaksandra Radzisheuskaya, Anne Laugesen, Jens Vilstrup Johansen, Daniel Geoffrey Hayward, Jakob Nilsson, Karl Agger, Kristian Helin
Chromatin-associated proteins are essential for the specification and maintenance of cell identity. They exert these functions through modulating and maintaining transcriptional patterns. To elucidate the functions of the Jmjd2 family of H3K9/H3K36 histone demethylases, we generated conditional Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1 single, double and triple knockout mouse embryonic stem cells (ESCs). We report that while individual Jmjd2 family members are dispensable for ESC maintenance and embryogenesis, combined deficiency for specifically Jmjd2a and Jmjd2c leads to early embryonic lethality and impaired ESC self-renewal, with spontaneous differentiation towards primitive endoderm under permissive culture conditions...
July 15, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27257215/jmjd2-kdm4-demethylases-are-required-for-expression-of-il3ra-and-survival-of-acute-myeloid-leukemia-cells
#6
Karl Agger, Satoru Miyagi, Marianne Terndrup Pedersen, Susanne M Kooistra, Jens Vilstrup Johansen, Kristian Helin
Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using Jmjd2a, Jmjd2b, and Jmjd2c conditional triple-knockout mice, we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene...
June 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/26741168/8-substituted-pyrido-3-4-d-pyrimidin-4-3h-one-derivatives-as-potent-cell-permeable-kdm4-jmjd2-and-kdm5-jarid1-histone-lysine-demethylase-inhibitors
#7
Vassilios Bavetsias, Rachel M Lanigan, Gian Filippo Ruda, Butrus Atrash, Mark G McLaughlin, Anthony Tumber, N Yi Mok, Yann-Vaï Le Bihan, Sally Dempster, Katherine J Boxall, Fiona Jeganathan, Stephanie B Hatch, Pavel Savitsky, Srikannathasan Velupillai, Tobias Krojer, Katherine S England, Jimmy Sejberg, Ching Thai, Adam Donovan, Akos Pal, Giuseppe Scozzafava, James M Bennett, Akane Kawamura, Catrine Johansson, Aleksandra Szykowska, Carina Gileadi, Nicola A Burgess-Brown, Frank von Delft, Udo Oppermann, Zoe Walters, Janet Shipley, Florence I Raynaud, Susan M Westaway, Rab K Prinjha, Oleg Fedorov, Rosemary Burke, Christopher J Schofield, Isaac M Westwood, Chas Bountra, Susanne Müller, Rob L M van Montfort, Paul E Brennan, Julian Blagg
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay...
February 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26364928/kdm4-jmjd2-histone-demethylase-inhibitors-block-prostate-tumor-growth-by-suppressing-the-expression-of-ar-and-bmyb-regulated-genes
#8
Lingling Duan, Ganesha Rai, Carlos Roggero, Qing-Jun Zhang, Qun Wei, Shi Hong Ma, Yunyun Zhou, John Santoyo, Elisabeth D Martinez, Guanghua Xiao, Ganesh V Raj, Ajit Jadhav, Anton Simeonov, David J Maloney, Josep Rizo, Jer-Tsong Hsieh, Zhi-Ping Liu
Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR...
September 17, 2015: Chemistry & Biology
https://www.readbyqxmd.com/read/26225543/an-iridium-iii-complex-inhibits-jmjd2-activities-and-acts-as-a-potential-epigenetic-modulator
#9
Li-Juan Liu, Lihua Lu, Hai-Jing Zhong, Bingyong He, Daniel W J Kwong, Dik-Lung Ma, Chung-Hang Leung
A novel iridium(III) complex was synthesized and evaluated for its ability to target JMJD2 enzymatic activity. The iridium(III) complex 1 can inhibit JMJD2 activity and was selective for JMJD2 activity over JARID, JMJD3, and HDAC activities. Moreover, 1 suppressed the trimethylation of the p21 promoter on H3K9me3 and interrupted the JMJD2D-H3K9me3 interactions in human cells, suggesting that it could act as an epigenetic modulator. To our knowledge, 1 represents the first metal-based JMJD2 inhibitor reported in the literature...
August 27, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26094604/epigenetic-regulation-of-embryonic-stem-cell-marker-mir302c-in-human-chondrosarcoma-as-determinant-of-antiproliferative-activity-of-proline-rich-polypeptide-1
#10
Karina Galoian, Amir Qureshi, Gianluca D'Ippolito, Paul C Schiller, Marco Molinari, Andrea L Johnstone, Shaun P Brothers, Ana C Paz, H T Temple
Metastatic chondrosarcoma of mesenchymal origin is the second most common bone malignancy and does not respond either to chemotherapy or radiation; therefore, the search for new therapies is relevant and urgent. We described recently that tumor growth inhibiting cytostatic proline-rich polypeptide 1, (PRP-1) significantly upregulated tumor suppressor miRNAs, downregulated onco-miRNAs in human chondrosarcoma JJ012 cell line, compared to chondrocytes culture. In this study we hypothesized the existence and regulation of a functional marker in cancer stem cells, correlated to peptides antiproliferative activity...
August 2015: International Journal of Oncology
https://www.readbyqxmd.com/read/25961932/h3k9me3-facilitates-hypoxia-induced-p53-dependent-apoptosis-through-repression-of-apak
#11
M M Olcina, K B Leszczynska, J M Senra, N F Isa, H Harada, E M Hammond
Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner...
February 11, 2016: Oncogene
https://www.readbyqxmd.com/read/25473037/inhibition-of-lsd1-reduces-herpesvirus-infection-shedding-and-recurrence-by-promoting-epigenetic-suppression-of-viral-genomes
#12
James M Hill, Debra C Quenelle, Rhonda D Cardin, Jodi L Vogel, Christian Clement, Fernando J Bravo, Timothy P Foster, Marta Bosch-Marce, Priya Raja, Jennifer S Lee, David I Bernstein, Philip R Krause, David M Knipe, Thomas M Kristie
Herpesviruses are highly prevalent and maintain lifelong latent reservoirs, thus posing challenges to the control of herpetic disease despite the availability of antiviral pharmaceuticals that target viral DNA replication. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 (lysine-specific demethylase 1) and a member of the JMJD2 family (Jumonji C domain-containing protein 2)...
December 3, 2014: Science Translational Medicine
https://www.readbyqxmd.com/read/24971742/kdm4b-as-a-target-for-prostate-cancer-structural-analysis-and-selective-inhibition-by-a-novel-inhibitor
#13
Chia-Han Chu, Ling-Yu Wang, Kai-Cheng Hsu, Chung-Chin Chen, Hsing-Hung Cheng, Szu-Min Wang, Chien-Ming Wu, Tsan-Jan Chen, Ling-Ting Li, Ruiwu Liu, Chiu-Lien Hung, Jing-Moon Yang, Hsing-Jien Kung, Wen-Ching Wang
The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site...
July 24, 2014: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/24953653/gps2-kdm4a-pioneering-activity-regulates-promoter-specific-recruitment-of-ppar%C3%AE
#14
M Dafne Cardamone, Bogdan Tanasa, Michelle Chan, Carly T Cederquist, Jaclyn Andricovich, Michael G Rosenfeld, Valentina Perissi
Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however, the regulatory strategies underlying each factor's effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of peroxisome proliferator-activator receptor γ (PPARγ) in adipocytes requires G protein suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2...
July 10, 2014: Cell Reports
https://www.readbyqxmd.com/read/24936217/pro-growth-role-of-the-jmjd2c-histone-demethylase-in-hct-116-colon-cancer-cells-and-identification-of-curcuminoids-as-jmjd2-inhibitors
#15
Tae-Dong Kim, James R Fuchs, Eric Schwartz, Dalia Abdelhamid, Jonathan Etter, William L Berry, Chenglong Li, Michael A Ihnat, Pui-Kai Li, Ralf Janknecht
Colon tumors are a major cause of cancer death, yet their molecular intricacies are not fully understood. We demonstrate that the histone demethylases JMJD2A, JMJD2B and JMJD2C are overexpressed in colon cancer cell lines, whereas another related protein, JMJD2D, is not. Interestingly, despite their high homology, the intracellular localization of JMJD2A-C is different in colon and other cancer cells, with JMJD2A being present comparably in the cytoplasm and nucleus, JMJD2B more prevalent in the nucleus and JMJD2C strongly associated with chromatin...
2014: American Journal of Translational Research
https://www.readbyqxmd.com/read/24325601/pan-histone-demethylase-inhibitors-simultaneously-targeting-jumonji-c-and-lysine-specific-demethylases-display-high-anticancer-activities
#16
Dante Rotili, Stefano Tomassi, Mariarosaria Conte, Rosaria Benedetti, Marcello Tortorici, Giuseppe Ciossani, Sergio Valente, Biagina Marrocco, Donatella Labella, Ettore Novellino, Andrea Mattevi, Lucia Altucci, Anthony Tumber, Clarence Yapp, Oliver N F King, Richard J Hopkinson, Akane Kawamura, Christopher J Schofield, Antonello Mai
In prostate cancer, two different types of histone lysine demethylases (KDM), LSD1/KDM1 and JMJD2/KDM4, are coexpressed and colocalize with the androgen receptor. We designed and synthesized hybrid LSD1/JmjC or "pan-KDM" inhibitors 1-6 by coupling the skeleton of tranylcypromine 7, a known LSD1 inhibitor, with 4-carboxy-4'-carbomethoxy-2,2'-bipyridine 8 or 5-carboxy-8-hydroxyquinoline 9, two 2-oxoglutarate competitive templates developed for JmjC inhibition. Hybrid compounds 1-6 are able to simultaneously target both KDM families and have been validated as potential antitumor agents in cells...
January 9, 2014: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/24219278/the-oncogenic-potential-of-jumonji-d2-jmjd2-kdm4-histone-demethylase-overexpression
#17
REVIEW
Leah C Young, Michael J Hendzel
The Jumonji D2 proteins (JMJD2/KDM4) function to demethylate di- and trimethylated (me2/3) histone 3 lysine 9 (H3K9me2/3) and H3K36me3. Knockout mouse models for Kdm4b and Kdm4d have not resulted in gross abnormalities, while mouse models for Kdm4a and Kdm4c have not been reported. However, the KDM4 subfamily of demethylases are overexpressed in several tumor types. Overexpression of KDM4 proteins alters transcription and chromatin remodeling, driving cellular proliferation, anchorage-independent growth, invasion, and migration...
December 2013: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/23692052/structural-investigations-of-the-nickel-induced-inhibition-of-truncated-constructs-of-the-jmjd2-family-of-histone-demethylases-using-x-ray-absorption-spectroscopy
#18
Nitai Charan Giri, Lisa Passantino, Hong Sun, Maria Antonietta Zoroddu, Max Costa, Michael J Maroney
Occupational and/or environmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in the accumulation of Ni(II) ions in cells. One group of major targets of Ni(II) ions inside the cell consists of Fe(II)- and αKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that the JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and αKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions...
June 18, 2013: Biochemistry
https://www.readbyqxmd.com/read/23644528/kdm4-jmjd2-histone-demethylases-epigenetic-regulators-in-cancer-cells
#19
REVIEW
William L Berry, Ralf Janknecht
Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ~130-kDa proteins (KDM4A-C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity...
May 15, 2013: Cancer Research
https://www.readbyqxmd.com/read/23451023/h3k56me3-is-a-novel-conserved-heterochromatic-mark-that-largely-but-not-completely-overlaps-with-h3k9me3-in-both-regulation-and-localization
#20
Antonia P M Jack, Silva Bussemer, Matthias Hahn, Sebastian Pünzeler, Martha Snyder, Michael Wells, Gyorgyi Csankovszki, Irina Solovei, Gunnar Schotta, Sandra B Hake
Histone lysine (K) methylation has been shown to play a fundamental role in modulating chromatin architecture and regulation of gene expression. Here we report on the identification of histone H3K56, located at the pivotal, nucleosome DNA entry/exit point, as a novel methylation site that is evolutionary conserved. We identify trimethylation of H3K56 (H3K56me3) as a modification that is present during all cell cycle phases, with the exception of S-phase, where it is underrepresented on chromatin. H3K56me3 is a novel heterochromatin mark, since it is enriched at pericentromeres but not telomeres and is thereby similar, but not identical, to the localization of H3K9me3 and H4K20me3...
2013: PloS One
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