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Histone demethylases

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https://www.readbyqxmd.com/read/29339836/the-role-of-metabolic-enzymes-in-mesenchymal-tumors-and-tumor-syndromes-genetics-pathology-and-molecular-mechanisms
#1
REVIEW
Inga-Marie Schaefer, Jason L Hornick, Judith V M G Bovée
The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite (D)-2-hydroxyglutarate...
January 16, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29339538/e6-protein-expressed-by-high-risk-hpv-activates-super-enhancers-of-the-egfr-and-c-met-oncogenes-by-destabilizing-the-histone-demethylase-kdm5c
#2
Xiaohua Chen, Jun Xian Loo, Xin Shi, Wenjun Xiong, Yong Guo, Haiqiang Ke, Mingkun Yang, Yanping Jiang, Siyu Xia, Min Zhao, Shan Zhong, ChunJiang He, Li Fu, Feng Li
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner...
January 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29339137/oxygen-induced-alterations-in-the-expression-of-chromatin-modifying-enzymes-and-the-transcriptional-regulation-of-imprinted-genes
#3
William M Skiles, Avery Kester, Jane H Pryor, Mark E Westhusin, Michael C Golding, Charles R Long
Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a...
January 12, 2018: Gene Expression Patterns: GEP
https://www.readbyqxmd.com/read/29336484/epigenetic-regulation-of-megakaryocytic-and-erythroid-differentiation-by-phf2-histone-demethylase
#4
Jichun Yang, Jing Ma, Yu Xiong, Yanlin Wang, Kaiyue Jin, Wenjun Xia, Qing Chen, Jianbo Huang, Jin Zhang, Nan Jiang, Shayi Jiang, Duan Ma
Plant homeodomain finger 2 (PHF2) is a JmjC family histone demethylase that demethylates H3K9me2, a repressive gene marker. PHF2 was found to play a role in the differentiation of several tissue types such as osteoblast and adipocyte differentiation. We report here that PHF2 plays a role in the epigenetic regulation of megakaryocytic (MK) and erythroid differentiation. We investigated PHF2 expression during MK and erythroid differentiation in K562 and human CD34+ progenitor (hCD34+ ) cells. Our data demonstrate that PHF2 expression is down-regulated during megakaryopoiesis and erythropoiesis...
January 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29335520/hpv16-e6-and-e7-upregulate-the-histone-lysine-demethylase-kdm2b-through-the-c-myc-mir-146a-5p-axys
#5
Elektra Peta, Alessandro Sinigaglia, Giulia Masi, Barbara Di Camillo, Angela Grassi, Marta Trevisan, Lorenzo Messa, Arianna Loregian, Erminia Manfrin, Matteo Brunelli, Guido Martignoni, Giorgio Palù, Luisa Barzon
Persistent infection by high-risk human papillomaviruses (HPVs) is associated with the development of cervical cancer and a subset of anogenital and head and neck squamous cell carcinomas. Abnormal expression of cellular microRNAs (miRNAs) plays an important role in the development of cancer, including HPV-related tumors. In this study, we demonstrated that miR-146a-5p was down-regulated by E6 and, less efficiently, by E7 of high-risk HPV16 in keratinocytes and the presence of low levels of this miRNA in cervical carcinoma cell lines and in high-risk HPV-positive cervical specimens...
January 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29331452/design-synthesis-and-evaluation-of-%C3%AE-turn-mimetics-as-lsd1-selective-inhibitors
#6
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity...
January 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29330049/the-histone-demethylase-phf8-promotes-adult-acute-lymphoblastic-leukemia-through-interaction-with-the-mek-erk-signaling-pathway
#7
Yue Fu, Yaling Yang, Xiaoming Wang, Xiaolin Yin, Minran Zhou, Siqi Wang, Lin Yang, Tao Huang, Man Xu, Chunyan Chen
Adult acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that is associated with a high risk of relapse and poor prognosis. Thus, novel pathogenic mechanisms and therapeutic targets need to be explored. Histone methylation is one of the most significant chromatin post-translational modifications. Here, we show that the histone demethylase PHF8 is highly expressed in a large number of ALL clinical specimens and that PHF8 expression is associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes the apoptosis of ALL cells in vitro as well as attenuates tumor growth in vivo...
January 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29324315/histone-demethylase-kdm5a-inhibits-glioma-cells-migration-and-invasion-by-down-regulating-zeb1
#8
Bin Dai, Hui Huang, Feng Guan, Guangtong Zhu, Zhiyong Xiao, Beibei Mao, Haiyang Su, Zhiqiang Hu
Malignant gliomas are highly lethal cancers worldwide as tumor cells infiltrate to healthy brain tissue invariably. Histone demethylase KDM5A as an oncogene or tumor suppressor in cancer still has been controversial. KDM5A may have a different function in different type cancer cells. However, the specific roles of KDM5A in the progression of glioma remain undiscovered. In this study, we found that compared with primary glioma, metastasis glioma had low KDM5A levels. Besides, lower KDM5A levels were linked to poor survival in glioma cancer patients, indicating that KDM5A is a new prognostic marker for glioma cancer...
January 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29321178/transcription-factor-dependent-anti-repressive-mammalian-enhancers-exclude-h3k27me3-from-extended-genomic-domains
#9
Madhurima Saxena, Adrianna K San Roman, Nicholas K O'Neill, Rita Sulahian, Unmesh Jadhav, Ramesh A Shivdasani
Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we identified hundreds of tissue-restricted enhancers that require the transcription factor (TF) CDX2 to prevent the incursion of H3K27me3 from adjoining areas of elevated basal marking into large well-demarcated genome domains...
January 10, 2018: Genes & Development
https://www.readbyqxmd.com/read/29317619/phf8-histone-demethylase-deficiency-causes-cognitive-impairments-through-the-mtor-pathway
#10
Xuemei Chen, Shuai Wang, Ying Zhou, Yanfei Han, Shengtian Li, Qing Xu, Longyong Xu, Ziqi Zhu, Youming Deng, Lu Yu, Lulu Song, Adele Pin Chen, Juan Song, Eiki Takahashi, Guang He, Lin He, Weidong Li, Charlie Degui Chen
Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 (Phf8) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29311580/lsd1-activation-promotes-inducible-emt-programs-and-modulates-the-tumour-microenvironment-in-breast-cancer
#11
T Boulding, R D McCuaig, A Tan, K Hardy, F Wu, J Dunn, M Kalimutho, C R Sutton, J K Forwood, A G Bert, G J Goodall, L Malik, D Yip, J E Dahlstrom, A Zafar, K K Khanna, S Rao
Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29303998/linking-dna-damage-and-age-related-promoter-dna-hyper-methylation-in-the-intestine
#12
Torsten Thalheim, Maria Herberg, Joerg Galle
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs...
January 5, 2018: Genes
https://www.readbyqxmd.com/read/29302039/targeting-the-corest-complex-with-dual-histone-deacetylase-and-demethylase-inhibitors
#13
Jay H Kalin, Muzhou Wu, Andrea V Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J Roberts, Justin M Roberts, Polina Prusevich, Jeliazko R Jeliazkov, Shourya S Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M Proby, Albena T Dinkova-Kostova, Wayne W Hancock, Jeffrey J Gray, James E Bradner, Sergio Valente, Antonello Mai, Nicole M Anders, Michelle A Rudek, Yong Hu, Byungwoo Ryu, John W R Schwabe, Andrea Mattevi, Rhoda M Alani, Philip A Cole
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes...
January 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29301935/-inhibition-of-histone-h3k27-demethylase-selectively-modulates-inflammatory-phenotypes-of-natural-killer-cells
#14
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...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29298815/genome-wide-characterisation-of-dna-methylation-in-an-invasive-lepidopteran-pest-the-cotton-bollworm-helicoverpa-armigera
#15
Christopher M Jones, Ka S Lim, Jason W Chapman, Chris Bass
The genes and genomes of insect pests are shaped by the wide array of selective forces encountered in their environments. While the molecular adaptations that evolve are beginning to be understood at the genomic and transcriptomic level they have been less well characterised at an epigenetic level. Here, we present a genome-wide map of DNA methylation, at single-nucleotide resolution for the cotton bollworm moth, Helicoverpa armigera; a globally invasive pest of agriculture. We show that methylation is almost identical in the larvae and adults of H...
January 3, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29290786/kdm5b-overexpression-predicts-a-poor-prognosis-in-patients-with-squamous-cell-carcinoma-of-the-head-and-neck
#16
Donghai Huang, Yuanzheng Qiu, Guo Li, Chao Liu, Li She, Diekuo Zhang, Xiyu Chen, Gangcai Zhu, Xin Zhang, Yongquan Tian, Yong Liu
Purpose: Lysine demethylase (KDM) 5B, as a member of the histone lysine demethylase family, is overexpressed and functions abnormally in various human cancers. However, its expression in the squamous cell carcinoma of the head and neck (SCCHN) remains unclear. Methods: KDM5B expression was analyzed by immunohistochemistry and correlated with clinicopathological parameters in 103 archival SCCHN tissue samples and 24 adjacent noncancerous epithelial tissues. Results: We found that KDM5B expression was higher in SCCHN than that in adjacent noncancerous tissues...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29289682/l-ascorbic-acid-a-true-substrate-for-hif-proly-hydroxylase
#17
A I Osipyants, A A Poloznikov, N A Smirnova, D M Hushpulian, A Yu Khristichenko, T A Chubar, A A Zakhariants, M Ahuja, I N Gaisina, B Thomas, A M Brown, I G Gazaryan, V I Tishkov
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif...
December 28, 2017: Biochimie
https://www.readbyqxmd.com/read/29281729/histone-demethylase-lsd1-restricts-influenza-a-virus-infection-by-erasing-ifitm3-k88-monomethylation
#18
Jiaoyu Shan, Binbin Zhao, Zhao Shan, Jia Nie, Rong Deng, Rui Xiong, Andy Tsun, Weiqi Pan, Hanzhi Zhao, Ling Chen, Ying Jin, Zhikang Qian, Kawing Lui, Rui Liang, Dan Li, Bing Sun, Dimitri Lavillette, Ke Xu, Bin Li
The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated. Here, we identify that, contrary to its role in enhancing DNA virus replication, LSD1 limits RNA virus replication by demethylating and activating IFITM3 which is a host restriction factor for many RNA viruses...
December 27, 2017: PLoS Pathogens
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...
December 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29276005/histone-lysine-methylases-and-demethylases-in-the-landscape-of-human-developmental-disorders
#20
Víctor Faundes, William G Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J Davies, Michelle K Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J Parker, Julia Rankin, Lisa Robertson, I Karen Temple, Siddharth Banka
Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs...
January 4, 2018: American Journal of Human Genetics
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