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Barbara Cascella, Soon Goo Lee, Sukrit Singh, Joseph M Jez, Liviu M Mirica
JIB-04, a specific inhibitor of the O2-activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O2 in KDM4A/JMJD2A through a continuous O2-consumption assay, X-ray crystal structure data, and molecular docking.
February 9, 2017: Chemical Communications: Chem Comm
Charlie Marvalim, Jing Xiang Gimson Wong, Natalia Sutiman, Wan Teck Lim, Shao Weng Tan, Ravindran Kanesvaran, Quan Sing Ng, Amit Jain, Mei Kim Ang, Wan Ling Tan, Chee Keong Toh, Eng Huat Tan, Balram Chowbay
The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1...
March 2017: Pharmacogenetics and Genomics
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...
February 20, 2017: ACS Chemical Biology
Gianluigi Franci, Federica Sarno, Angela Nebbioso, Lucia Altucci
Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete...
October 21, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Ling-Yu Wang, Chiu-Lien Hung, Yun-Ru Chen, Joy C Yang, Junjian Wang, Mel Campbell, Yoshihiro Izumiya, Hong-Wu Chen, Wen-Ching Wang, David K Ann, Hsing-Jien Kung
The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation...
September 13, 2016: Cell Reports
Mélissa Carbonneau, Laurence M Gagné, Marie-Eve Lalonde, Marie-Anne Germain, Alena Motorina, Marie-Christine Guiot, Blandine Secco, Emma E Vincent, Anthony Tumber, Laura Hulea, Jonathan Bergeman, Udo Oppermann, Russell G Jones, Mathieu Laplante, Ivan Topisirovic, Kevin Petrecca, Marc-Étienne Huot, Frédérick A Mallette
The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases...
September 14, 2016: Nature Communications
Junjian Wang, Haibin Wang, Ling-Yu Wang, Demin Cai, Zhijian Duan, Yanhong Zhang, Peng Chen, June X Zou, Jianzhen Xu, Xinbin Chen, Hsing-Jien Kung, Hong-Wu Chen
Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death...
November 1, 2016: Cell Death and Differentiation
Bo Wang, Xinxin Fan, Chong Ma, Hui Lei, Qianfa Long, Yuan Chai
Glioma is the most common type of primary intracranial tumor and has a poor prognosis. It has been reported that lysine-specific demethylase 4A (KDM4A) can promote tumor progression; however, its role in human glioma remains unclear. Western blot and qRT-PCR analyses showed that KDM4A was highly expressed in U87MG and T98G cells. 48 h after transfection with siKDM4A, the protein level of KDM4A was significantly downregulated. The silenced expression of KDM4A in T98G or U87MG cells inhibited cell viability and invasion, and aggravated cell apoptosis...
October 2016: Journal of Molecular Neuroscience: MN
Ludovica Morera, Martin Roatsch, Michael C D Fürst, Inga Hoffmann, Johanna Senger, Mirjam Hau, Henriette Franz, Roland Schüle, Markus R Heinrich, Manfred Jung
Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs...
September 20, 2016: ChemMedChem
Suresh Ambati, Ping Yu, Elizabeth C McKinney, Muthugapatti K Kandasamy, Diane Hartzell, Clifton A Baile, Richard B Meagher
BACKGROUND: Obesity-related comorbidities are thought to result from the reprogramming of the epigenome in numerous tissues and cell types, and in particular, mature adipocytes within visceral and subcutaneous adipose tissue, VAT and SAT. The cell-type specific chromatin remodeling of mature adipocytes within VAT and SAT is poorly understood, in part, because of the difficulties of isolating and manipulating large fragile mature adipocyte cells from adipose tissues. METHODS: We constructed MA-INTACT (Mature Adipocyte-Isolation of Nuclei TAgged in specific Cell Types) mice using the adiponectin (ADIPOQ) promoter (ADNp) to tag the surface of mature adipocyte nuclei with a reporter protein...
2016: BMC Obesity
Kathleen Kylie, Julia Romero, Indeewari K S Lindamulage, James Knockleby, Hoyun Lee
The co-regulation of DNA replication and gene transcription is still poorly understood. To gain a better understanding of this important control mechanism, we examined the DNA replication and transcription using the Dbf4 origin-promoter and Dbf4 pseudogene models. We found that origin firing and Dbf4 transcription activity were inversely regulated in a cell cycle-dependent manner. We also found that proteins critical for the regulation of replication (ORC, MCM), transcription (SP1, TFIIB), and cohesin (Smc1, Smc3) and Mediator functions (Med1, Med12) interact with specific sites within and the surrounding regions of the Dbf4 locus in a cell cycle-dependent manner...
September 2016: Cell Cycle
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
Ping Yu, Lexiang Ji, Kevin J Lee, Miao Yu, Chuan He, Suresh Ambati, Elizabeth C McKinney, Crystal Jackson, Clifton A Baile, Robert J Schmitz, Richard B Meagher
The reprogramming of cellular memory in specific cell types, and in visceral adipocytes in particular, appears to be a fundamental aspect of obesity and its related negative health outcomes. We explored the hypothesis that adipose tissue contains epigenetically distinct subpopulations of adipocytes that are differentially potentiated to record cellular memories of their environment. Adipocytes are large, fragile, and technically difficult to efficiently isolate and fractionate. We developed fluorescence nuclear cytometry (FNC) and fluorescence activated nuclear sorting (FANS) of cellular nuclei from visceral adipose tissue (VAT) using the levels of the pan-adipocyte protein, peroxisome proliferator-activated receptor gamma-2 (PPARg2), to distinguish classes of PPARg2-Positive (PPARg2-Pos) adipocyte nuclei from PPARg2-Negative (PPARg2-Neg) leukocyte and endothelial cell nuclei...
2016: PloS One
Tae-Dong Kim, Sook Shin, Ralf Janknecht
ERG (ETS-related gene) is a member of the ETS (erythroblast transformation-specific) family of transcription factors. Overexpression of the ERG transcription factor is observed in half of all prostate tumors and is an underlying cause of this disease. However, the mechanisms involved in the functions of ERG are still not fully understood. In the present study, we showed that ERG can directly bind to KDM4A (also known as JMJD2A), a histone demethylase that particularly demethylates lysine 9 on histone H3. ERG and KDM4A cooperated in upregulating the promoter of Yes-associated protein 1 (YAP1), a downstream effector in the Hippo signaling pathway and crucial growth regulator...
June 2016: Oncology Reports
Hu Wang, Jie-Lan Ma, Ying-Gui Yang, Yang Song, Jiao Wu, Yan-Yan Qin, Xue-Li Zhao, Jun Wang, Li-Li Zou, Jiang-Feng Wu, Jun-Ming Li, Chang-Bai Liu
Cell-penetrating peptide (CPP) based delivery have provided immense potential for the therapeutic applications, however, most of nonhuman originated CPPs carry the risk of possible cytotoxicity and immunogenicity, thus may restricting to be used. Here, we describe a novel human-derived CPP, denoted hPP10, and hPP10 has cell-penetrating properties evaluated by CellPPD web server, as well as In-Vitro and In-Vivo analysis. In vitro studies showed that hPP10-FITC was able to penetrate into various cells including primary cultured cells, likely through an endocytosis pathway...
August 2, 2016: Oncotarget
Jeoung Eun Lee, Young Gie Chung, Jin Hee Eum, Yumie Lee, Dong Ryul Lee
Although three different research groups have reported successful derivations of human somatic cell nuclear transfer-derived embryonic stem cell (SCNT-ESC) lines using fetal, neonatal and adult fibroblasts, the extremely poor development of cloned embryos has hindered its potential applications in regenerative medicine. Recently, however, our group discovered that the severe methylation of lysine 9 in Histone H3 in a human somatic cell genome was a major SCNT reprogramming barrier, and the overexpression of KDM4A, a H3K9me3 demethylase, significantly improved the blastocyst formation of SCNT embryos...
April 2016: BMB Reports
Mathieu Neault, Frédérick A Mallette, Stéphane Richard
Activating K-Ras mutations occurs frequently in pancreatic cancers and is implicated in their development. Cancer-initiating events, such as oncogenic Ras activation, lead to the induction of cellular senescence, a tumor suppressor response. During senescence, the decreased levels of KDM4A lysine demethylase contribute to p53 activation, however, the mechanism by which KDM4A is downregulated is unknown. We show that miR-137 targets KDM4A mRNA during Ras-induced senescence and activates both p53 and retinoblastoma (pRb) tumor suppressor pathways...
March 1, 2016: Cell Reports
Yoshikazu Johmura, Jia Sun, Kyoko Kitagawa, Keiko Nakanishi, Toshiya Kuno, Aya Naiki-Ito, Yumi Sawada, Tomomi Miyamoto, Atsushi Okabe, Hiroyuki Aburatani, ShengFan Li, Ichiro Miyoshi, Satoru Takahashi, Masatoshi Kitagawa, Makoto Nakanishi
Recent evidence has revealed that senescence induction requires fine-tuned activation of p53, however, mechanisms underlying the regulation of p53 activity during senescence have not as yet been clearly established. We demonstrate here that SCF(Fbxo22)-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCF(Fbxo22) ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A...
February 12, 2016: Nature Communications
Magdalena Korczynska, Daniel D Le, Noah Younger, Elisabet Gregori-Puigjané, Anthony Tumber, Tobias Krojer, Srikannathasan Velupillai, Carina Gileadi, Radosław P Nowak, Eriko Iwasa, Samuel B Pollock, Idelisse Ortiz Torres, Udo Oppermann, Brian K Shoichet, Danica Galonić Fujimori
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations...
February 25, 2016: Journal of Medicinal Chemistry
Gareth W Langley, Anne Brinkø, Martin Münzel, Louise J Walport, Christopher J Schofield, Richard J Hopkinson
The dynamic post-translational modifications of histones play important roles in the regulation of transcription in animals. The demethylation of N(ε)-methyl lysine residues in the N-terminal tail of histone H3 is catalyzed by demethylases, of which the largest family is the ferrous iron and 2-oxoglutarate dependent demethylases (JmjC KDMs), which catalyze demethylation via initial hydroxylation of the N-methyl groups. We report studies on the conformational requirements of the JmjC KDM substrates using N-methylated lysine analogues prepared by metathesis reactions of suitably protected N-allylglycine...
March 18, 2016: ACS Chemical Biology
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