keyword
MENU ▼
Read by QxMD icon Read
search

KDM4

keyword
https://www.readbyqxmd.com/read/29126261/heme-promotes-transcriptional-and-demethylase-activities-of-gis1-a-member-of-the-histone-demethylase-jmjd2-kdm4-family
#1
Sneha Lal, Jonathan M Comer, Purna C Konduri, Ajit Shah, Tianyuan Wang, Anthony Lewis, Grant Shoffner, Feng Guo, Li Zhang
The yeast Gis1 protein is a transcriptional regulator belonging to the JMJD2/KDM4 subfamily of demethylases that contain a JmjC domain, which are highly conserved from yeast to humans. They have important functions in histone methylation, cellular signaling and tumorigenesis. Besides serving as a cofactor in many proteins, heme is known to directly regulate the activities of proteins ranging from transcriptional regulators to potassium channels. Here, we report a novel mechanism governing heme regulation of Gis1 transcriptional and histone demethylase activities...
November 6, 2017: Nucleic Acids Research
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/28883001/kdm4-inhibition-targets-breast-cancer-stem-like-cells
#3
Eric Metzger, Stella S Stepputtis, Juliane Strietz, Bogdan-Tiberius Preca, Sylvia Urban, Dominica Willmann, Anita Allen, Fides Zenk, Nicola Iovino, Peter Bronsert, Amelie Proske, Marie Follo, Melanie Boerries, Elmar Stickeler, Jiangchun Xu, Michael B Wallace, Jeffrey A Stafford, Toufike Kanouni, Jochen Maurer, Roland Schüle
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy...
September 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28835804/design-of-kdm4-inhibitors-with-antiproliferative-effects-in-cancer-models
#4
Young K Chen, Tiziana Bonaldi, Alessandro Cuomo, Joselyn R Del Rosario, David J Hosfield, Toufike Kanouni, Shih-Chu Kao, Chon Lai, Neethan A Lobo, Jennifer Matuszkiewicz, Andrew McGeehan, Shawn M O'Connell, Lihong Shi, Jeffrey A Stafford, Ryan K Stansfield, James M Veal, Michael S Weiss, Natalie Y Yuen, Michael B Wallace
Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models...
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#5
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
July 18, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28407004/epigenetically-repressing-human-cytomegalovirus-lytic-infection-and-reactivation-from-latency-in-thp-1-model-by-targeting-h3k9-and-h3k27-histone-demethylases
#6
Xin Gan, Haifeng Wang, Yanyan Yu, Wei Yi, Shanshan Zhu, En Li, Yu Liang
Human Cytomegalovirus (hCMV) infects a broad range of the population and establishes life-long latency in the infected individuals. Periodically the latently infected virus can reactivate and becomes a significant cause of morbidity and mortality in immunocompromised individuals. In latent infection, the viral genome is suppressed in a heterochromatic state and viral gene transcription is silenced. Upon reactivation, the repressive chromatin is remodeled to an active form, allowing viral lytic gene transcription, initiated by the expression of viral Immediate Early (IE) genes...
2017: PloS One
https://www.readbyqxmd.com/read/28346812/identification-of-a-novel-benzimidazole-pyrazolone-scaffold-that-inhibits-kdm4-lysine-demethylases-and-reduces-proliferation-of-prostate-cancer-cells
#7
David M Carter, Edgar Specker, Jessica Przygodda, Martin Neuenschwander, Jens Peter von Kries, Udo Heinemann, Marc Nazaré, Ulrich Gohlke
Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment...
August 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#8
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28278055/comparative-analyses-identify-molecular-signature-of-mri-classified-svz-associated-glioblastoma
#9
COMPARATIVE STUDY
Chin-Hsing Annie Lin, Christopher T Rhodes, ChenWei Lin, Joanna J Phillips, Mitchel S Berger
Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM...
April 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28087629/jmjd2c-facilitates-the-assembly-of-essential-enhancer-protein-complexes-at-the-onset-of-embryonic-stem-cell-differentiation
#10
Rute A Tomaz, Jennifer L Harman, Donja Karimlou, Lauren Weavers, Lauriane Fritsch, Tony Bou-Kheir, Emma Bell, Ignacio Del Valle Torres, Kathy K Niakan, Cynthia Fisher, Onkar Joshi, Hendrik G Stunnenberg, Edward Curry, Slimane Ait-Si-Ali, Helle F Jørgensen, Véronique Azuara
Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we reveal that Jmjd2c facilitates this process by stabilising the assembly of mediator-cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while Jmjd2c-knockout ESCs remain capable of forming extra-embryonic endoderm derivatives...
February 15, 2017: Development
https://www.readbyqxmd.com/read/28051298/the-activity-of-jmjc-histone-lysine-demethylase-kdm4a-is-highly-sensitive-to-oxygen-concentrations
#11
Rebecca L Hancock, Norma Masson, Kate Dunne, Emily Flashman, Akane Kawamura
The JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG)-dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations...
April 21, 2017: ACS Chemical Biology
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
#12
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...
March 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27709909/engineering-biological-c-h-functionalization-leads-to-allele-specific-regulation-of-histone-demethylases
#13
Megan Breski, Debasis Dey, Sara Obringer, Babu Sudhamalla, Kabirul Islam
Oxidative C-H hydroxylation of methyl groups, followed by their removal from DNA, RNA or histones, is an epigenetic process critical to transcriptional reprogramming and cell fate determination. This reaction is catalyzed by Fe(II)-dependent dioxygenases using the essential metabolite 2-ketoglutarate (2KG) as a cofactor. Given that the human genome encodes for more than 60 2KG-dependent dioxygenases, assigning their individual functions remains a significant challenge. Here we describe a protein-ligand interface engineering approach to break the biochemical degeneracy of these enzymes...
October 6, 2016: Journal of the American Chemical Society
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
#14
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...
January 2017: 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
#15
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...
2016: Anticancer Research
https://www.readbyqxmd.com/read/27618572/pyrido-3-4-d-pyrimidin-4-3h-one-metabolism-mediated-by-aldehyde-oxidase-is-blocked-by-c2-substitution
#16
Angela Hayes, N Yi Mok, Manjuan Liu, Ching Thai, Alan T Henley, Butrus Atrash, Rachel M Lanigan, Jemmy Sejberg, Yann-Vaï Le Bihan, Vassilios Bavetsias, Julian Blagg, Florence I Raynaud
1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and (1)H-NMR and showed that C2-substituted derivatives are no longer AO substrates...
September 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27506941/kdm4b-plays-an-important-role-in-mitochondrial-apoptosis-by-upregulating-hax1-expression-in-colorectal-cancer
#17
Haijie Li, Xi Yang, Guihua Wang, Xiaolan Li, Deding Tao, Junbo Hu, Xuelai Luo
Histone methyltransferases and demethylases regulate transcription by altering the epigenetic marks on histones in tumorigenesis. Members of the histone lysine(K)-specific demethylase 4 (KDM4) family are dysregulated in several types of cancer. Here, we report a novel role for KDM4B in mitochondrial apoptosis. In this study, we demonstrate that KDM4B is overexpressed in colorectal cancer (CRC) tissues. Decreased expression of KDM4B significantly promoted apoptosis of CRC cell lines. Moreover, our data indicate that HAX1 is required for KDM4B-mediated mitochondrial apoptosis...
September 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27257215/jmjd2-kdm4-demethylases-are-required-for-expression-of-il3ra-and-survival-of-acute-myeloid-leukemia-cells
#18
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/27214403/structural-analysis-of-human-kdm5b-guides-histone-demethylase-inhibitor-development
#19
Catrine Johansson, Srikannathasan Velupillai, Anthony Tumber, Aleksandra Szykowska, Edward S Hookway, Radoslaw P Nowak, Claire Strain-Damerell, Carina Gileadi, Martin Philpott, Nicola Burgess-Brown, Na Wu, Jola Kopec, Andrea Nuzzi, Holger Steuber, Ursula Egner, Volker Badock, Shonagh Munro, Nicholas B LaThangue, Sue Westaway, Jack Brown, Nick Athanasou, Rab Prinjha, Paul E Brennan, Udo Oppermann
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families...
July 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/26747609/opposing-chromatin-signals-direct-and-regulate-the-activity-of-lysine-demethylase-4c-kdm4c
#20
Lindsey R Pack, Keith R Yamamoto, Danica Galonić Fujimori
Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 9 trimethylation (H3K9me3) are epigenetic marks with opposing roles in transcription regulation. Whereas colocalization of these modifications is generally excluded in the genome, how this preclusion is established remains poorly understood. Lysine demethylase 4C (KDM4C), an H3K9me3 demethylase, localizes predominantly to H3K4me3-containing promoters through its hybrid tandem tudor domain (TTD) (1, 2), providing a model for how these modifications might be excluded...
March 18, 2016: Journal of Biological Chemistry
keyword
keyword
64802
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"