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Histone demethylases

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https://www.readbyqxmd.com/read/28722470/novel-potent-inhibitors-of-the-histone-demethylase-kdm1a-lsd1-orally-active-in-a-murine-promyelocitic-leukemia-model
#1
Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello
BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor...
July 19, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28720390/epigenetic-regulation-of-epithelial-to-mesenchymal-transition-by-the-lysine-specific-demethylase-lsd1-kdm1a
#2
REVIEW
Susanna Ambrosio, Carmen D Saccà, Barbara Majello
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners...
July 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28717873/orchestration-of-h3k27-methylation-mechanisms-and-therapeutic-implication
#3
REVIEW
Mei-Ren Pan, Ming-Chuan Hsu, Li-Tzong Chen, Wen-Chun Hung
Histone proteins constitute the core component of the nucleosome, the basic unit of chromatin. Chemical modifications of histone proteins affect their interaction with genomic DNA, the accessibility of recognized proteins, and the recruitment of enzymatic complexes to activate or diminish specific transcriptional programs to modulate cellular response to extracellular stimuli or insults. Methylation of histone proteins was demonstrated 50 years ago; however, the biological significance of each methylated residue and the integration between these histone markers are still under intensive investigation...
July 17, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28717007/epigenetic-suppression-of-human-telomerase-htert-is-mediated-by-the-metastasis-suppressor-nme2-in-a-g-quadruplex-dependent-fashion
#4
Dhurjhoti Saha, Ankita Singh, Tabish Hussain, Vivek Srivastava, Suman Sengupta, Anirban Kar, Parashar Dhapola, Vishnu Dhople, Ramesh Ummani, Shantanu Chowdhury
Transcriptional activation of the human telomerase reverse transcriptase (hTERT) gene, which remains repressed in adult somatic cells, is critical during tumorigenesis. Several transcription factors and the epigenetic state of the hTERT promoter are known to be important for tight control of hTERT in normal tissues, but the molecular mechanisms leading to hTERT reactivation in cancer are not well understood. Surprisingly, here we found occupancy of the metastasis suppressor nonmetastatic 2 (NME2) within hTERT core promoter in HT1080 fibrosarcoma cells and HCT116 colon cancer cells, and NME2 mediated transcriptional repression of hTERT in these cells...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28706564/vitamin-c-induces-specific-demethylation-of-h3k9me2-in-mouse-embryonic-stem-cells-via-kdm3a-b
#5
Kevin T Ebata, Kathryn Mesh, Shichong Liu, Misha Bilenky, Alexander Fekete, Michael G Acker, Martin Hirst, Benjamin A Garcia, Miguel Ramalho-Santos
BACKGROUND: Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. RESULTS: We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in naïve ES cells...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28706445/histone-demethylase-kdm2b-upregulates-histone-methyltransferase-ezh2-expression-and-contributes-to-the-progression-of-ovarian-cancer-in-vitro-and-in-vivo
#6
Yan Kuang, Fangfang Lu, Jianfeng Guo, Hong Xu, Qi Wang, Chaohuan Xu, Longjia Zeng, Suyi Yi
Aberrant histone methylation contributes to the progression and development of many tumors. Histone methylation is a dynamic process regulated by both histone demethylase and histone methyltransferase, which ultimately alters the levels of gene transcription. However, the relationship between histone demethylase and histone methyltransferase, as well as their regulatory mechanisms in ovarian cancer development, is still unclear. Lysine-specific demethylase 2B (KDM2B) is a key demethylase of H3K36me3 and H3K4me3 that regulates gene expression and plays a role in tumorigenesis via epigenetic mechanisms...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28705010/isocitrate-dehydrogenase-mutation-as-a-therapeutic-target-in-gliomas
#7
Catherine H Han, Tracy T Batchelor
Isocitrate dehydrogenases (IDH) are important enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. More than 80% of low-grade gliomas and secondary glioblastoma (GBM) harbor an IDH mutation. IDH mutations involve the catalytic pocket of the enzyme and lead to a neomorphic ability to produce 2-hydroxyglutarate (2HG) while oxidizing NADPH to NADP+. 2HG is considered as an 'oncometabolite' which is thought to be responsible for many, if not all, biologic effects of IDH mutations...
June 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28701701/systematic-discovery-of-genetic-modulation-by-jumonji-histone-demethylases-in-drosophila
#8
Nevine A Shalaby, Raheel Sayed, Qiao Zhang, Shane Scoggin, Susan Eliazer, Adrian Rothenfluh, Michael Buszczak
Jumonji (JmjC) domain proteins influence gene expression and chromatin organization by way of histone demethylation, which provides a means to regulate the activity of genes across the genome. JmjC proteins have been associated with many human diseases including various cancers, developmental and neurological disorders, however, the shared biology and possible common contribution to organismal development and tissue homeostasis of all JmjC proteins remains unclear. Here, we systematically tested the function of all 13 Drosophila JmjC genes...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28701475/hif-activation-causes-synthetic-lethality-between-the-vhl-tumor-suppressor-and-the-ezh1-histone-methyltransferase
#9
Abhishek A Chakraborty, Eijiro Nakamura, Jun Qi, Amanda Creech, Jacob D Jaffe, Joshiawa Paulk, Jesse S Novak, Kshithija Nagulapalli, Samuel K McBrayer, Glenn S Cowley, Javier Pineda, Jiaxi Song, Yaoyu E Wang, Steven A Carr, David E Root, Sabina Signoretti, James E Bradner, William G Kaelin
Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity...
July 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28701172/vitamin-c-induces-specific-demethylation-of-h3k9me2-in-mouse-embryonic-stem-cells-via-kdm3a-b
#10
Kevin T Ebata, Kathryn Mesh, Shichong Liu, Misha Bilenky, Alexander Fekete, Michael G Acker, Martin Hirst, Benjamin A Garcia, Miguel Ramalho-Santos
BACKGROUND: Histone methylation patterns regulate gene expression and are highly dynamic during development. The erasure of histone methylation is carried out by histone demethylase enzymes. We had previously shown that vitamin C enhances the activity of Tet enzymes in embryonic stem (ES) cells, leading to DNA demethylation and activation of germline genes. RESULTS: We report here that vitamin C induces a remarkably specific demethylation of histone H3 lysine 9 dimethylation (H3K9me2) in naïve ES cells...
July 12, 2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28699367/a-comprehensive-review-of-lysine-specific-demethylase-1-and-its-roles-in-cancer
#11
Amir Hosseini, Saverio Minucci
Histone methylation plays a key role in the regulation of chromatin structure, and its dynamics regulates important cellular processes. The investigation of the role of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Lysine-specific demethylase 1(LSD1, also known as KDM1A) is the first discovered histone lysine demethylase, with the ability to demethylase H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner...
July 12, 2017: Epigenomics
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...
July 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28693517/jmjd2a-promotes-the-warburg-effect-and-nasopharyngeal-carcinoma-progression-by-transactivating-ldha-expression
#13
Yi Su, Qiu-Hong Yu, Xiang-Yun Wang, Li-Ping Yu, Zong-Feng Wang, Ying-Chun Cao, Jian-Dong Li
BACKGROUND: Jumonji C domain 2A (JMJD2A), as a histone demethylases, plays a vital role in tumorigenesis and progression. But, its functions and underlying mechanisms of JMJD2A in nasopharyngeal carcinoma (NPC) metabolism are remained to be clarified. In this study, we investigated glycolysis regulation by JMJD2A in NPC and the possible mechanism. METHODS: JMJD2A expression was detected by Western blotting and Reverse transcription quantitative real-time PCR analysis...
July 11, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28692045/impact-of-histone-demethylase-kdm3a-dependent-ap-1-transactivity-on-hepatotumorigenesis-induced-by-pi3k-activation
#14
T Nakatsuka, K Tateishi, Y Kudo, K Yamamoto, H Nakagawa, H Fujiwara, R Takahashi, K Miyabayashi, Y Asaoka, Y Tanaka, H Ijichi, Y Hirata, M Otsuka, M Kato, J Sakai, M Tachibana, H Aburatani, Y Shinkai, K Koike
Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28687800/pkc%C3%AE-mediated-phosphorylation-of-lsd1-is-required-for-presynaptic-plasticity-and-hippocampal-learning-and-memory
#15
Chae-Seok Lim, Hye Jin Nam, Jaehyun Lee, Dongha Kim, Ja Eun Choi, SukJae Joshua Kang, Somi Kim, Hyopil Kim, Chuljung Kwak, Kyu-Won Shim, Siyong Kim, Hyoung-Gon Ko, Ro Un Lee, Eun-Hae Jang, Juyoun Yoo, Jaehoon Shim, Md Ariful Islam, Yong-Seok Lee, Jae-Hyung Lee, Sung Hee Baek, Bong-Kiun Kaang
Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKCα was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1 (SA/SA) knock-in (KI) mice, in which a PKCα phosphorylation site is mutated...
July 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28684529/targeting-histone-demethylases-in-myc-driven-neuroblastomas-with-ciclopirox
#16
Jun Yang, Sandra Milasta, Dongli Hu, Alaa AlTahan, Rodrigo Interiano, Junfang Zhou, Jesse Davidson, Jonathan Low, Wenwei Lin, Ju Bao, Pollyanna Goh, Amit Nathwani, Ruoning Wang, Yingdi Wang, Su Sien Ong, Vincent Boyd, Brandon Young, Sourav Das, Anang A Shelat, Yinan Wu, Zhenmei Li, Jie Zheng, Ashutosh Mishra, Yong Cheng, Chunxu Qu, Junmin Peng, Douglas R Green, Stephen White, R Kip Guy, Taosheng Chen, Andrew Davidoff
Histone lysine demethylases facilitate the activity of oncogenic transcription factors including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells where MYC is often overexpressed. We also identified the approved small molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation...
July 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/28684291/lysine-demethylase-inhibition-protects-pancreatic-%C3%AE-cells-from-apoptosis-and-improves-%C3%AE-cell-function
#17
Marie Balslev Backe, Jan Legaard Andersson, Karl Bacos, Dan Ploug Christensen, Jakob Bondo Hansen, Jerzy Jòzef Dorosz, Michael Gajhede, Tina Dahlby, Madhusudhan Bysani, Line Hyltoft Kristensen, Charlotte Ling, Lars Olsen, Thomas Mandrup-Poulsen
Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction...
July 4, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28678843/kshv-encoded-orf59-modulates-histone-arginine-methylation-of-the-viral-genome-to-promote-viral-reactivation
#18
Roxanne C Strahan, Maria McDowell-Sargent, Timsy Uppal, Pravinkumar Purushothaman, Subhash C Verma
Kaposi's sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into 'open' chromatin through the involvement of lysine demethylases and methyltransferases. Besides methylation of lysine residues of histone H3, arginine methylation of histone H4 plays an important role in controlling the compactness of the chromatin. Symmetric methylation of histone H4 at arginine 3 (H4R3me2s) negatively affects the methylation of histone H3 at lysine 4 (H3K4me3), an active epigenetic mark deposited on the viral chromatin during reactivation...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28661478/kdm2b-an-h3k36-specific-demethylase-regulates-apoptotic-response-of-gbm-cells-to-trail
#19
Ibrahim Cagri Kurt, Ilknur Sur, Ezgi Kaya, Ahmet Cingoz, Selena Kazancioglu, Zeynep Kahya, Omer Duhan Toparlak, Filiz Senbabaoglu, Zeynep Kaya, Ezgi Ozyerli, Sercin Karahüseyinoglu, Nathan A Lack, Zeynep H Gümüs, Tamer T Onder, Tugba Bagci-Onder
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28658622/lanosterol-modulates-tlr4-mediated-innate-immune-responses-in-macrophages
#20
Elisa Araldi, Marta Fernández-Fuertes, Alberto Canfrán-Duque, Wenwen Tang, Gary W Cline, Julio Madrigal-Matute, Jordan S Pober, Miguel A Lasunción, Dianqing Wu, Carlos Fernández-Hernando, Yajaira Suárez
Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression...
June 27, 2017: Cell Reports
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