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Lysine specific demethylase

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https://www.readbyqxmd.com/read/28642444/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#1
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634230/similarity-in-gene-regulatory-networks-suggests-that-cancer-cells-share-characteristics-of-embryonic-neural-cells
#2
Zan Zhang, Anhua Lei, Liyang Xu, Lu Chen, Yonglong Chen, Xuena Zhang, Yan Gao, Xiaoli Yang, Min Zhang, Ying Cao
Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and re-differentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that, inhibition of the epigenetic modification enzymes enhancer of zeste homolog 2 (EZH2), histone deacetylases (HDACs) 1 and 3, lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines...
June 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28627608/silencing-of-lsd1-gene-modulates-histone-methylation-and-acetylation-and-induces-the-apoptosis-of-jeko-1-and-molt-4-cells
#3
Zhong-Kai Zou, Yi-Qun Huang, Yong Zou, Xu-Ke Zheng, Xu-Dong Ma
Lysine-specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics; however, the pathological roles of its dysfunction in mantle cell lymphoma (MCL) and T-cell acute lymphoblastic leukemia remain to be elucidated. In this study, we evaluated LSD1, and histone H3 lysine 4 (H3K4)me1 and H3K4me2 expression in patients with MCL and silenced LSD1 in JeKo‑1 and MOLT‑4 cells, in order to define its role in JeKo‑1 and MOLT‑4 cell proliferation and apoptosis. We retrospectively analyzed the protein expression of LSD1, and mono- and dimethylated H3K4 (H3K4me1 and H3K4me2), and cyclin D1 and Ki67 in 30 cases of MCL by immunohistochemistry...
June 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28617441/concomitant-epigenetic-targeting-of-lsd1-and-hdac-synergistically-induces-mitochondrial-apoptosis-in-rhabdomyosarcoma-cells
#4
Tinka Haydn, Eric Metzger, Roland Schuele, Simone Fulda
The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28611094/agonist-specific-protein-interactomes-of-glucocorticoid-and-androgen-receptor-as-revealed-by-proximity-mapping
#5
Joanna K Lempiäinen, Einari A Niskanen, Kaisa-Mari Vuoti, Riikka E Lampinen, Helka Göös, Markku Varjosalo, Jorma J Palvimo
Glucocorticoid receptor (GR) and androgen receptor (AR) are steroid-inducible transcription factors (TFs). GR and AR are central regulators of various metabolic, homeostatic and differentiation processes and hence important therapeutic targets, especially in inflammation and prostate cancer, respectively. Hormone binding to these steroid receptors (SRs) leads to DNA binding and activation or repression of their target genes with the aid of interacting proteins, coregulators. However, protein interactomes of these important drug targets have remained poorly defined...
June 13, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28610981/3d-qsar-comfa-comsia-molecular-docking-and-molecular-dynamics-simulations-study-of-6-aryl-5-cyano-pyrimidine-derivatives-to-explore-the-structure-requirements-of-lsd1-inhibitors
#6
Lina Ding, Zhi-Zheng Wang, Xu-Dong Sun, Jing Yang, Chao-Ya Ma, Wen Li, Hong-Min Liu
Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models...
May 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28597915/dissecting-lsd1-dependent-neuronal-maturation-in-the-olfactory-epithelium
#7
Julie H Coleman, Brian Lin, James E Schwob
Neurons in the olfactory epithelium (OE) each express a single dominant olfactory receptor (OR) allele from among roughly 1000 different OR genes. While monogenic and monoallelic OR expression has been appreciated for over two decades, regulators of this process are still being described; most recently, epigenetic modifiers have been of high interest as silent OR genes are decorated with transcriptionally-repressive trimethylated histone 3 lysine 9 (H3K9me3) whereas active OR genes are decorated with transcriptionally-activating trimethylated histone 3 lysine 4 (H3K4me3)...
June 9, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28587848/mir-148a-3p-regulates-adipocyte-and-osteoblast-differentiation-by-targeting-lysine-specific-demethylase-6b
#8
Lijie Tian, Fang Zheng, Zhijia Li, Haixiao Wang, Hairui Yuan, Xin Zhang, Zhongshu Ma, Xiaoxia Li, Xiumei Gao, Baoli Wang
Recent emerging studies of miRNAs in mesenchymal stem cell commitment toward adipocyte and osteoblast provide new insights for the understanding of the molecular basis of adipogenesis and osteogenesis. The current study revealed that miR-148a-3p was altered in primary cultured marrow stromal cells and established stromal ST2 line after adipogenic and/or osteogenic treatment. Supplementing miR-148a-3p activity inhibited cell growth and induced ST2 to differentiate into mature adipocytes. Conversely, inactivation of the endogenous miR-148a-3p suppressed ST2 to fully differentiate...
June 3, 2017: Gene
https://www.readbyqxmd.com/read/28571892/lpe-1-an-orally-active-pyrimidine-derivative-inhibits-growth-and-mobility-of-human-esophageal-cancers-by-targeting-lsd1
#9
Bo Wang, Bing Zhao, Lu-Ping Pang, Yuan-Di Zhao, Qian Guo, Jun-Wei Wang, Yi-Chao Zheng, Xin-Hui Zhang, Ying Liu, Guang-Yao Liu, Wen-Ge Guo, Chao Wang, Zhong-Hua Li, Xue-Jing Mao, Bin Yu, Li-Ying Ma, Hong-Min Liu
Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0...
May 30, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28545974/development-of-5-hydroxypyrazole-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#10
Daniel P Mould, Ulf Bremberg, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Helen F Small, Tim C P Somervaille, Donald Ogilvie
A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86...
May 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28534506/lsd1-demethylates-hif1%C3%AE-to-inhibit-hydroxylation-and-ubiquitin-mediated-degradation-in-tumor-angiogenesis
#11
J-Y Lee, J-H Park, H-J Choi, H-Y Won, H-S Joo, D-H Shin, M K Park, B Han, K P Kim, T J Lee, C M Croce, G Kong
Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis...
May 22, 2017: Oncogene
https://www.readbyqxmd.com/read/28487543/kdm6b-modulates-mapk-pathway-mediating-multiple-myeloma-cell-growth-and-survival
#12
H Ohguchi, T Harada, M Sagawa, S Kikuchi, Y-T Tai, P G Richardson, T Hideshima, K C Anderson
Recent studies have delineated cancer type-specific roles of histone 3 lysine 27 (H3K27) demethylase KDM6B/JMJD3 depending on its H3K27 demethylase activity. Here we show that KDM6B is expressed in multiple myeloma (MM); and that shRNA-mediated knockdown and CRISPR-mediated knockout of KDM6B abrogate MM cell growth and survival. TNFα or bone marrow stromal cell culture supernatants induce KDM6B, which is blocked by IKKβ inhibitor MLN120B, suggesting KDM6B is regulated by NF-κB signaling in MM cells. RNA-sequencing and subsequent ChIP-qPCR analyses reveal that KDM6B is recruited to the loci of genes encoding components of MAPK signaling pathway including ELK1 and FOS, and upregulates these genes expression without affecting H3K27 methylation level...
May 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28486922/an-overview-on-screening-methods-for-lysine-specific-demethylase-1-lsd1-inhibitors
#13
Yi-Chao Zheng, Jiao Chang, Ting Zhang, Feng-Zhi Suo, Xiao-Bing Chen, Ying Liu, Bing Zhao, Bin Yu, Hong-Min Liu
BACKGROUND: In the past few years, lots of attention has been given to the identification and characterization of selective and potent inhibitors of the first identified histone demethylase LSD1, which may erase mono- and di-methylated histone 3 lysine 4 and 9. As the aberrant overexpression of LSD1 is involved in various pathological processes, especially cancer, obtaining selective and potent LSD1 inhibitors has emerged as a crucial issue in medicinal chemistry research. METHOD: Until now, several LSD1 inhibitor screening models have been established, including enzyme coupled assay, LC-MS based assay, FRET based assay...
May 8, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28484864/genome-wide-association-study-identifies-loci-associated-with-resistance-to-viral-nervous-necrosis-disease-in-asian-seabass
#14
Le Wang, Peng Liu, Shuqing Huang, Baoqing Ye, Elaine Chua, Zi Yi Wan, Gen Hua Yue
Viral nervous necrosis disease (VNN), caused by nervous necrosis virus (NNV), is one major threat to mariculture. Identifying loci and understanding the mechanisms associated with resistance to VNN are important in selective breeding programs. We performed a genome-wide association study (GWAS) using genotyping-by-sequencing (GBS) to study the genomic architecture of resistance to NNV infection in Asian seabass. We genotyped 986 individuals from 43 families produced by 15 founders with 44498 bi-allelic genetic variants using GBS...
May 8, 2017: Marine Biotechnology
https://www.readbyqxmd.com/read/28481366/the-zinc-finger-transcriptional-factor-slug-transcriptionally-downregulates-er%C3%AE-by-recruiting-lysine-specific-demethylase-1-in-human-breast-cancer
#15
J-W Bai, M-N Chen, X-L Wei, Y-Ch Li, H-Y Lin, M Chen, J-W Li, C-W Du, K Man, G-J Zhang
Estrogen receptor α (ERα) is related with epithelial-mesenchymal transition, invasion and metastasis, and serves as an important therapeutic predictor and prognostic factor in breast cancer patients. The triple negative breast cancer (TNBC) is characterized by loss of hormone receptors and human epidermal growth factor receptor 2 (Her2), and lacks effective targeted therapy with poor prognosis. Unfortunately, the molecular mechanisms of ERα deficiency, which becomes hormone independent and results in resistance to endocrine therapy, remain to be elucidated in breast cancer...
May 8, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28461471/lsd1-prevents-age-programed-loss-of-beige-adipocytes
#16
Delphine Duteil, Milica Tosic, Dominica Willmann, Anastasia Georgiadi, Toufike Kanouni, Roland Schüle
Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28460360/design-synthesis-and-biological-activity-of-3-oxoamino-benzenesulfonamides-as-selective-and-reversible-lsd1-inhibitors
#17
Jiayue Xi, Siyuan Xu, Liming Wu, Tianfang Ma, Rongfeng Liu, Yu-Chih Liu, Dawei Deng, Yueqing Gu, Jinpei Zhou, Fei Lan, Xiaoming Zha
Lysine specific demethylase 1 (LSD1) is a flavin-dependent amine oxidase that selectively removes one or two methyl groups from H3 at Lys4 and is recognized as a promising therapeutic target for cancer and other diseases. Here, a series of 3-oxoamino-benzenesulfonamides were synthesized and evaluated for their inhibitory activity against LSD1. Compounds 7b and 7h showed the most potent inhibition with the IC50 values of 9.5 and 6.9μM, respectively. Furthermore, the LSD1 inhibition of 7b and 7h were reversible and selective...
June 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28450737/writing-erasing-and-reading-histone-lysine-methylations
#18
REVIEW
Kwangbeom Hyun, Jongcheol Jeon, Kihyun Park, Jaehoon Kim
Histone modifications are key epigenetic regulatory features that have important roles in many cellular events. Lysine methylations mark various sites on the tail and globular domains of histones and their levels are precisely balanced by the action of methyltransferases ('writers') and demethylases ('erasers'). In addition, distinct effector proteins ('readers') recognize specific methyl-lysines in a manner that depends on the neighboring amino-acid sequence and methylation state. Misregulation of histone lysine methylation has been implicated in several cancers and developmental defects...
April 28, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28439316/epigenetic-assays-for-chemical-biology-and-drug-discovery
#19
REVIEW
Sheraz Gul
The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28435523/discovery-of-1-2-3-triazolo-4-5-d-pyrimidine-derivatives-as-novel-lsd1-inhibitors
#20
Zhong-Hua Li, Xue-Qi Liu, Peng-Fei Geng, Feng-Zhi Suo, Jin-Lian Ma, Bin Yu, Tao-Qian Zhao, Zhao-Qing Zhou, Chen-Xi Huang, Yi-Chao Zheng, Hong-Min Liu
Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure-activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound 27 as potent LSD1 inhibitor (IC50 = 0...
April 13, 2017: ACS Medicinal Chemistry Letters
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