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https://www.readbyqxmd.com/read/29769286/targeted-inhibition-of-histone-h3k27-demethylation-is-effective-in-high-risk-neuroblastoma
#1
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29752294/utx-promotes-chromatin-remodeling-to-suppress-leukemogenesis
#2
(no author information available yet)
UTX-mediated suppression of myeloid leukemogenesis is independent of its demethylase activity.
May 11, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29751094/the-interest-of-women-with-mayer-rokitansky-k%C3%A3-ster-hauser-syndrome-and-laparoscopic-vecchietti-neovagina-in-uterus-transplantation
#3
Roman Chmel, Marta Novackova, Zlatko Pastor, Jiri Fronek
STUDY OBJECTIVE: The goal of this study was to assess a group of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) women with surgically created neovaginas in the interest of uterus transplantation (UTx) and to recruit the first group of applicants for a uterus transplant trial. DESIGN: and Setting: This is an original prospective study using semistructured interviews. PARTICIPANTS: A study group of 50 MRKH syndrome women with Vecchietti neovaginas was recruited by letter of invitation...
May 8, 2018: Journal of Pediatric and Adolescent Gynecology
https://www.readbyqxmd.com/read/29740925/metformin-directly-targets-the-h3k27me3-demethylase-kdm6a-utx
#4
Elisabet Cuyàs, Sara Verdura, Laura Llorach-Pares, Salvador Fernández-Arroyo, Fedra Luciano-Mateo, Noemí Cabré, Jan Stursa, Lukas Werner, Begoña Martin-Castillo, Benoit Viollet, Jiri Neuzil, Jorge Joven, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Javier A Menendez
Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX...
May 8, 2018: Aging Cell
https://www.readbyqxmd.com/read/29736013/utx-mediated-enhancer-and-chromatin-remodeling-suppresses-myeloid-leukemogenesis-through-noncatalytic-inverse-regulation-of-ets-and-gata-programs
#5
Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J Knights, Mercedes Pardo, Lu Yu, Jyoti S Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, Ignacio Varela, Ruben Bautista, Grace Collord, Oliver Dovey, Dimitrios A Garyfallos, Etienne De Braekeleer, Saki Kondo, Jonathan Cooper, Berthold Göttgens, Lars Bullinger, Paul A Northcott, David Adams, George S Vassiliou, Brian J P Huntly
The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss...
May 7, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29682321/use-of-biomedical-photonics-in-gynecological-surgery-a-uterine-transplantation-model
#6
Srdjan Saso, Neil T Clancy, Benjamin P Jones, Timothy Bracewell-Milnes, Maya Al-Memar, Eleanor M Cannon, Simran Ahluwalia, Joseph Yazbek, Meen-Yau Thum, Tom Bourne, Daniel S Elson, James Richard Smith, Sadaf Ghaem-Maghami
Aim: Uterine transplantation (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility. The study aims were to compare pulse oximetry and multispectral imaging (MSI), for intraoperative tracking of uterine oxygen saturation in animal UTx models (rabbit and sheep). Results/methodology: Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Comparison of oxygen saturation   values between the pre-UTx donor and post-UTx recipient, and pre-UTx and post-UTx recipient reveals a statistically significant decrease in saturation levels post-UTx...
April 2018: Future Science OA
https://www.readbyqxmd.com/read/29551674/utx-affects-neural-stem-cell-proliferation-and-differentiation-through-pten-signaling
#7
Xuepei Lei, Jianwei Jiao
Neural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation and decreases terminal mitosis and neuronal differentiation...
March 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29542684/exosomes-from-suxiao-jiuxin-pill-treated-cardiac-mesenchymal-stem-cells-decrease-h3k27-demethylase-utx-expression-in-mouse-cardiomyocytes-in-vitro
#8
Xiao-Fen Ruan, Yong-Jun Li, Cheng-Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu-Tao Liu, Il-Man Kim, Xiao-Long Wang, Neal L Weintraub, Yao-Liang Tang
Suxiao Jiuxin Pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms...
March 15, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29530603/modulation-of-the-endocrine-transcriptional-program-by-targeting-histone-modifiers-of-the-h3k27me3-mark
#9
Marta Fontcuberta-PiSunyer, Sara Cervantes, Eulàlia Miquel, Sergio Mora-Castilla, Louise C Laurent, Angel Raya, Ramon Gomis, Rosa Gasa
Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells...
March 9, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29524724/a-survey-of-public-opinion-in-the-united-states-regarding-uterine-transplantation
#10
Eduardo Hariton, Pietro Bortoletto, Randi H Goldman, Leslie V Farland, Elizabeth S Ginsburg, Antonio R Gargiulo
OBJECTIVE: Our objective was to evaluate opinions and attitudes of the general public regarding uterine transplantation (UTx) in the United States (U.S.). DESIGN: Cross-sectional study (Canadian Task Force Classification II-2) SETTING: Web-based survey. PATIENTS(S): Nationally representative sample of adult U.S. residents by age and gender. INTERVENTION(S): Web-based questionnaire administered in November 2016. MAIN OUTCOME MEASURE(S): Respondents who supported UTx were compared with those who were opposed using log binomial regression to calculate relative risk ratios and 95% confidence intervals RESULT(S): Of the 1,444 respondents recruited, 1,337 (93%) completed the survey...
March 7, 2018: Journal of Minimally Invasive Gynecology
https://www.readbyqxmd.com/read/29483212/inhibition-of-the-histone-h3k27-demethylase-utx-enhances-tumor-cell-radiosensitivity
#11
Barbara H Rath, Isabella Waung, Kevin Camphausen, Philip J Tofilon
The processes mediating the repair of DNA double-strand breaks (DSB) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications, including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines...
May 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29479368/the-histone-demethylase-jmjd2a-modulates-the-induction-of-hypertrophy-markers-in-ipsc-derived-cardiomyocytes
#12
Wendy Rosales, Fernando Lizcano
The development of cardiovascular pathologies is partly attributed to epigenetic causes, including histone methylation, which appears to be an important marker in hearts that develop cardiac hypertrophy. Previous studies showed that the histone demethylase JMJD2A can regulate the hypertrophic process in murine cardiomyocytes. However, the influence of JMJD2A on cardiac hypertrophy in a human cardiomyocyte model is still poorly understood. In the present study, cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) were used...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29479066/utx-loss-causes-myeloid-transformation
#13
Liting Zheng, Longyong Xu, Qing Xu, Lu Yu, Danfeng Zhao, Pu Chen, Wei Wang, Yiqin Wang, Gang Han, Charlie Degui Chen
Recurrent somatic loss-of-function mutations in histone demethylases are frequently detected in cancer. However, whether loss of a histone demethylase can cause cancer has not been determined. Here, we report that knockout of the histone demethylase Utx in mice causes a chronic myelomonocytic leukemia (CMML)-like disease with splenomegaly, monocytosis, and extramedullary hematopoiesis. Mutational analysis of patient data indicated that UTX mutations occur simultaneously with TP53 mutations in myeloid malignancies, and combined inactivation of Utx and Trp53 accelerated the development of CMML in a cell-autonomous manner...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29421189/utx-moonlighting-in-the-cytoplasm
#14
Ralf Wiedemuth, Sebastian Thieme, Katrin Navratiel, Benjamin Dorschner, Sebastian Brenner
The X-linked histone demethylase UTX has a pivotal role in cellular and developmental processes including embryogenesis, hematopoiesis and cancer. UTX removes di- and trimethyl groups on histone H3 lysine 27, thereby regulating gene expression. But there is growing evidence that UTX displays biological functions independent of its histone demethylase activity. To elucidate these novel functions, it is of great interest to define subcellular localizations of UTX. Here we show for the first time that native UTX is primarily localized in the cytoplasm whereas ectopic GFP and Flag-tagged UTX display nuclear and cytoplasmic localization...
April 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29351209/the-prognostic-significance-of-histone-demethylase-utx-in-esophageal-squamous-cell-carcinoma
#15
Shau-Hsuan Li, Hung-I Lu, Wan-Ting Huang, Wan-Yu Tien, Ya-Chun Lan, Wei-Che Lin, Hsin-Ting Tsai, Chang-Han Chen
The dysregulation of the ubiquitously transcribed TPR gene on the X chromosome ( UTX ) has been reported to be involved in the oncogenesis of several types of cancers. However, the expression and significance of UTX in esophageal squamous cell carcinoma (ESCC) remains largely undetermined. Immunohistochemistry was performed in 106 ESCC patients, and correlated with clinicopathological features and survival. The functional role of UTX in ESCC cells was determined by UTX -mediated siRNA. Univariate analyses showed that high UTX expression was associated with superior overall survival (OS, p = 0...
January 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29346574/systematic-genetic-interaction-studies-identify-histone-demethylase-utx-as-potential-target-for-ameliorating-huntington-s-disease
#16
Wan Song, Nóra Zsindely, Anikó Faragó, J Lawrence Marsh, László Bodai
No abstract text is available yet for this article.
February 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29301935/inhibition-of-histone-h3k27-demethylases-selectively-modulates-inflammatory-phenotypes-of-natural-killer-cells
#17
Adam Cribbs, Edward S Hookway, Graham Wells, Morten Lindow, Susanna Obad, Henrik Oerum, Rab K Prinjha, Nick Athanasou, Aneka Sowman, Martin Philpott, Henry Penn, Kalle Soderstrom, Marc Feldmann, Udo Oppermann
Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets...
February 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29283410/clinical-and-neurobehavioral-features-of-three-novel-kabuki-syndrome-patients-with-mosaic-kmt2d-mutations-and-a-review-of-literature
#18
Francesca Romana Lepri, Dario Cocciadiferro, Bartolomeo Augello, Paolo Alfieri, Valentina Pes, Alessandra Vancini, Cristina Caciolo, Gabriella Maria Squeo, Natascia Malerba, Iolanda Adipietro, Antonio Novelli, Stefano Sotgiu, Renzo Gherardi, Maria Cristina Digilio, Bruno Dallapiccola, Giuseppe Merla
Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX , two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p...
December 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29281014/systematic-genetic-interaction-studies-identify-histone-demethylase-utx-as-potential-target-for-ameliorating-huntington-s-disease
#19
Wan Song, Nóra Zsindely, Anikó Faragó, J Lawrence Marsh, László Bodai
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins...
February 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29259482/uterus-transplantation-toward-clinical-application-in-japan
#20
REVIEW
Nobuhiko Suganuma, Ayako Hayashi, Iori Kisu, Kouji Banno, Hisako Hara, Makoto Mihara
Background: In recent years, uterus transplantation (UTx) has been applied as the treatment for patients with uterine factor infertility worldwide. Thus, the clinical application of UTx in Japan should be considered through both the history of UTx technology development in the world and future prospects. Methods: Recent information on UTx was collected via a literature survey and the Internet. Results: Basic research using various animals has been done mainly since 2000...
October 2017: Reproductive Medicine and Biology
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