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https://www.readbyqxmd.com/read/29045832/utx-kdm6a-loss-enhances-the-malignant-phenotype-of-multiple-myeloma-and-sensitizes-cells-to-ezh2-inhibition
#1
Teresa Ezponda, Daphné Dupéré-Richer, Christine M Will, Eliza C Small, Nobish Varghese, Tej Patel, Behnam Nabet, Relja Popovic, Jon Oyer, Marinka Bulic, Yupeng Zheng, Xiaoxiao Huang, Mrinal Y Shah, Sayantan Maji, Alberto Riva, Manuela Occhionorelli, Giovanni Tonon, Neil Kelleher, Jonathan Keats, Jonathan D Licht
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29029452/the-h3k27me3-demethylase-kdm6a-is-suppressed-in-breast-cancer-stem-like-cells-and-enables-the-resolution-of-bivalency-during-the-mesenchymal-epithelial-transition
#2
Joseph H Taube, Nathalie Sphyris, Kelsey S Johnson, Keighley N Reisenauer, Taylor A Nesbit, Robiya Joseph, Geraldine V Vijay, Tapasree R Sarkar, Neeraja A Bhangre, Joon Jin Song, Jeffrey T Chang, Min Gyu Lee, Rama Soundararajan, Sendurai A Mani
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28968467/kdm6a-addiction-of-cervical-carcinoma-cell-lines-is-triggered-by-e7-and-mediated-by-p21cip1-suppression-of-replication-stress
#3
David R Soto, Christopher Barton, Karl Munger, Margaret E McLaughlin-Drubin
Expression of E7 proteins encoded by carcinogenic, high-risk human papillomaviruses (HPVs) triggers increased expression of the histone H3 lysine 27 demethylase KDM6A. KDM6A expression is necessary for survival of high-risk HPV E7 expressing cells, including several cervical cancer lines. Here we show that increased KDM6A in response to high-risk HPV E7 expression causes epigenetic de-repression of the cell cycle and DNA replication inhibitor p21CIP1, and p21CIP1 expression is necessary for survival of high-risk HPV E7 expressing cells...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28928876/heterochromatin-reduction-correlates-with-the-increase-of-the-kdm4b-and-kdm6a-demethylases-and-the-expression-of-pericentromeric-dna-during-the-acquisition-of-a-transformed-phenotype
#4
Cinthya Gurrion, Maritere Uriostegui, Mario Zurita
Cancer cells have alterations in chromatin organization, mostly a reduction in heterochromatin. How this process occurs during transformation and if it participates in the maintenance of a cancerous phenotype is not well understood. Here, using a transformation-inducible cell line, we analyzed the changes that occur in heterochromatin during transformation to a cancerous phenotype. After transformation, there is a reduction in heterochromatin bodies and a nuclear reorganization of HP1α. These occurrences correlate with reductions in H3K9me3 and H3K27me3 levels and with some of the enzymes that introduce these modifications...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28887033/long-term-exposure-to-pm2-5-lowers-influenza-virus-resistance-via-down-regulating-pulmonary-macrophage-kdm6a-and-mediates-histones-modification-in-il-6-and-ifn-%C3%AE-promoter-regions
#5
Jing-Hui Ma, Shao-Hua Song, Meng Guo, Ji Zhou, Fang Liu, Li Peng, Zhi-Ren Fu
Atmospheric particulates, especially PM2.5, not only damage the respiratory system, but also play important roles in pulmonary immunity. China is influenced by atmospheric diffusion conditions, industrial manufacturers, and heating and discharging. PM2.5 levels in the air rise substantially in the winter, which is also a period of flu high-incidence. Although an epidemiological link exists between PM2.5 and flu, we do not understand how long-term PM2.5 inhalation affects pulmonary immunity and the influenza virus response...
November 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28884922/congenital-heart-defects-in-molecularly-proven-kabuki-syndrome-patients
#6
Maria Cristina Digilio, Maria Gnazzo, Francesca Lepri, Maria Lisa Dentici, Elisa Pisaneschi, Anwar Baban, Chiara Passarelli, Rossella Capolino, Adriano Angioni, Antonio Novelli, Bruno Marino, Bruno Dallapiccola
The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%)...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28793284/growth-hormone-therapy-in-children-with-kabuki-syndrome-1-year-treatment-results
#7
Dina A Schott, Willem J M Gerver, Constance T R M Stumpel
BACKGROUND/AIMS: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. METHODS: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year...
2017: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/28758283/copy-number-profiling-of-adult-relapsed-b-cell-precursor-acute-lymphoblastic-leukemia-reveals-potential-leukemia-progression-mechanisms
#8
Jordi Ribera, Lurdes Zamora, Mireia Morgades, Mar Mallo, Neus Solanes, Montserrat Batlle, Susana Vives, Isabel Granada, Jordi Juncà, Roberto Malinverni, Eulàlia Genescà, Ramon Guàrdia, Santiago Mercadal, Lourdes Escoda, Joaquín Martinez-Lopez, Mar Tormo, Jordi Esteve, Marta Pratcorona, Carmen Martinez-Losada, Francesc Solé, Evarist Feliu, Josep-Maria Ribera
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays...
July 30, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28747563/the-h3k27me3-demethylase-kdm6a-is-suppressed-in-breast-cancer-stem-like-cells-and-enables-the-resolution-of-bivalency-during-the-mesenchymal-epithelial-transition
#9
Joseph H Taube, Nathalie Sphyris, Kelsey S Johnson, Keighley N Reisenauer, Taylor A Nesbit, Robiya Joseph, Geraldine V Vijay, Tapasree R Sarkar, Neeraja A Bhangre, Joon Jin Song, Jeffrey T Chang, Min Gyu Lee, Rama Soundararajan, Sendurai A Mani
The deposition of the activating H3K4me3 and repressive H3K27me3 histone modifications within the same promoter, forming a so-called bivalent domain, maintains gene expression in a repressed but transcription-ready state. We recently reported a significantly increased incidence of bivalency following an epithelial-mesenchymal transition (EMT), a process associated with the initiation of the metastatic cascade. The reverse process, known as the mesenchymal-epithelial transition (MET), is necessary for efficient colonization...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28725537/the-emerging-role-of-histone-demethylases-in-renal-cell-carcinoma
#10
REVIEW
Xiaoqiang Guo, Qiaoxia Zhang
Renal cell carcinoma (RCC), the most common kidney cancer, is responsible for more than 100,000 deaths per year worldwide. The molecular mechanism of RCC is poorly understood. Many studies have indicated that epigenetic changes such as DNA methylation, noncoding RNAs, and histone modifications are central to the pathogenesis of cancer. Histone demethylases (KDMs) play a central role in histone modifications. There is emerging evidence that KDMs such as KDM3A, KDM5C, KDM6A, and KDM6B play important roles in RCC...
2017: Journal of Kidney Cancer and VHL
https://www.readbyqxmd.com/read/28712054/alcohol-exposure-promotes-dna-methyltransferase-dnmt3a-upregulation-through-reactive-oxygen-species-dependent-mechanisms
#11
Federico Miozzo, Hélène Arnould, Aurélie de Thonel, Anne-Laure Schang, Délara Sabéran-Djoneidi, Anne Baudry, Benoît Schneider, Valérie Mezger
Abundant evidence has accumulated showing that fetal alcohol exposure broadly modifies DNA methylation profiles in the brain. DNA methyltransferases (DNMTs), the enzymes responsible for DNA methylation, are likely implicated in this process. However, their regulation by ethanol exposure has been poorly addressed. Here, we show that alcohol exposure modulates DNMT protein levels through multiple mechanisms. Using a neural precursor cell line and primary mouse embryonic fibroblasts (MEFs), we found that ethanol exposure augments the levels of Dnmt3a, Dnmt3b, and Dnmt3l transcripts...
July 15, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28698146/epigenetic-regulation-of-epithelial-mesenchymal-transition-by-kdm6a-histone-demethylase-in-lung-cancer-cells
#12
Minoru Terashima, Akihiko Ishimura, Sasithorn Wanna-Udom, Takeshi Suzuki
Histone methylation is associated with various biological and pathological processes including cancer development. KDM6A is a candidate tumor suppressor gene that encodes a histone H3 lysine 27 (H3K27) demethylase. In this study, we discovered that ectopic expression of KDM6A antagonized TGF-β-induced epithelial-mesenchymal transition (EMT) and cell migration of lung cancer cell lines through its demethylase activity. KDM6A counteracted TGF-β-dependent changes in the expression of EMT-related genes such as CDH1/E-cadherin, FN1/Fibronectin, ZEB family and microRNA-200 family...
September 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28695659/epstein-barr-virus-negative-extranodal-true-natural-killer-cell-lymphoma-harbouring-a-kdm6a-mutation
#13
Naoko Tsuyama, Reimi Asaka, Akito Dobashi, Satoko Baba, Yuko Mishima, Kyoko Ueda, Masahiko Oguchi, Hideki Tsuji, Kiyohiko Hatake, Kengo Takeuchi
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities...
July 10, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28694326/genomic-analysis-of-220-ctcls-identifies-a-novel-recurrent-gain-of-function-alteration-in-rltpr-p-q575e
#14
Joonhee Park, Jingyi Yang, Alexander T Wenzel, Akshaya Ramachandran, Wung J Lee, Jay C Daniels, Juhyun Kim, Estela Martinez-Escala, Nduka Amankulor, Barbara Pro, Joan Guitart, Marc L Mendillo, Jeffrey N Savas, Titus J Boggon, Jaehyuk Choi
Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA splicing (U2AF1), T-cell receptor signaling (PTPRN2, RLTPR), and T-cell differentiation (RARA)...
September 21, 2017: Blood
https://www.readbyqxmd.com/read/28665819/targeting-ezh2-in-cancer-therapy
#15
REVIEW
Makoto Yamagishi, Kaoru Uchimaru
PURPOSE OF REVIEW: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2). RECENT FINDINGS: Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types...
September 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28551381/a-specific-mutational-signature-associated-with-dna-8-oxoguanine-persistence-in-mutyh-defective-colorectal-cancer
#16
Alessandra Viel, Alessandro Bruselles, Ettore Meccia, Mara Fornasarig, Michele Quaia, Vincenzo Canzonieri, Eleonora Policicchio, Emanuele Damiano Urso, Marco Agostini, Maurizio Genuardi, Emanuela Lucci-Cordisco, Tiziana Venesio, Aline Martayan, Maria Grazia Diodoro, Lupe Sanchez-Mete, Vittoria Stigliano, Filomena Mazzei, Francesca Grasso, Alessandro Giuliani, Marta Baiocchi, Roberta Maestro, Giuseppe Giannini, Marco Tartaglia, Ludmil B Alexandrov, Margherita Bignami
8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours...
June 2017: EBioMedicine
https://www.readbyqxmd.com/read/28511912/inhibition-of-kdm4a-activity-as-a-strategy-to-suppress-interleukin-6-production-and-attenuate-colitis-induction
#17
Kazuhiro Ishiguro, Osamu Watanabe, Masanao Nakamura, Takeshi Yamamura, Masanobu Matsushita, Hidemi Goto, Yoshiki Hirooka
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production...
July 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28483946/p53-maintains-baseline-expression-of-multiple-tumor-suppressor-genes
#18
Kyrie Pappas, Jia Xu, Sakellarios Zairis, Lois Resnick-Silverman, Francesco Abate, Nicole Steinbach, Sait Ozturk, Lao H Saal, Tao Su, Pamela Cheung, Hank Schmidt, Stuart Aaronson, Hanina Hibshoosh, James Manfredi, Raul Rabadan, Ramon Parsons
TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes...
August 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28442529/coinheritance-of-novel-mutations-in-scn1a-causing-gefs-and-in-kdm6a-causing-kabuki-syndrome-in-a-family
#19
Jisun Kim, Cha Gon Lee
Because the differentiation between phenotypic expansion and blended phenotypes is not clear, the mixed phenotypes of blended rare genetic diseases make diagnosis difficult. We describe a family with the co-existence and co-segregation of generalized epilepsy with febrile seizures plus (GEFS+) and Kabuki syndrome (KS). The proband, a 7-year-old male, presented with GEFS+, dysmorphic facial features, short stature, developmental delay, and intellectual disability. Two novel missense mutations: p.G325A in the KDM6A gene responsible for KS and p...
March 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/28415684/the-long-noncoding-rna-linc-ned125-controls-the-expression-of-medulloblastoma-driver-genes-by-microrna-sponge-activity
#20
Pietro Laneve, Agnese Po, Annarita Favia, Ivano Legnini, Vincenzo Alfano, Jessica Rea, Valerio Di Carlo, Valeria Bevilacqua, Evelina Miele, Angela Mastronuzzi, Andrea Carai, Franco Locatelli, Irene Bozzoni, Elisabetta Ferretti, Elisa Caffarelli
Long noncoding RNAs (lncRNAs) are major regulators of physiological and disease-related gene expression, particularly in the central nervous system. Dysregulated lncRNA expression has been documented in several human cancers, and their tissue-specificity makes them attractive candidates as diagnostic/prognostic biomarkers and/or therapeutic agents. Here we show that linc-NeD125, which we previously characterized as a neuronal-induced lncRNA, is significantly overexpressed in Group 4 medulloblastomas (G4 MBs), the largest and least well characterized molecular MB subgroup...
May 9, 2017: Oncotarget
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