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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/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
#5
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/28601046/lsd1-knockdown-reveals-novel-histone-lysine-methylation-in-human-breast-cancer-mcf-7-cells
#6
Yue Jin, Bo Huo, Xueqi Fu, Zhongyi Cheng, Jun Zhu, Yu Zhang, Tian Hao, Xin Hu
Histone lysine methylation, which plays an important role in the regulation of gene expression, genome stability, chromosome conformation and cell differentiation, is a dynamic process that is collaboratively regulated by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). LSD1, the first identified KDMs, catalyzes the demethylation of mono- and di-methylated H3K4 and H3K9. Here, we systematically investigated the effects of LSD1 knockdown on histone methylations. Surprisingly, in addition to H3K4 and H3K9, the methylation level on other histone lysines, such as H3K27, H3K36 and H3K79, are also increased...
June 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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/28584023/notch-represses-transcription-by-prc2-recruitment-to-the-ternary-complex
#8
Xiaoqing Han, Prathibha Ranganathan, Christos Tzimas, Kelly L Weaver, Ke Jin, Luisana Astudillo, Wen Zhou, Xiaoxia Zhu, Bin Li, David J Robbins, Anthony J Capobianco
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner...
June 5, 2017: Molecular Cancer Research: MCR
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/28555890/the-dual-role-of-lesion-simulating-disease-1-as-a-condition-dependent-scaffold-protein-and-transcription-regulator
#10
Weronika Czarnocka, Katrien Van Der Kelen, Patrick Willems, Magdalena Szechynska-Hebda, Sara Shahnejat-Bushehri, Salma Balazadeh, Anna Rusaczonek, Bernd Mueller-Roeber, Frank Van Breusegem, Stanisław Karpinski
Since its discovery over two decades ago as an important cell death regulator in Arabidopsis thaliana, the role of LESION SIMULATING DISEASE 1 (LSD1) has been studied intensively within both biotic and abiotic stress responses as well as with respect to plant fitness regulation. However, its molecular mode of action remains enigmatic. Here we demonstrate that nucleo-cytoplasmic LSD1 interacts with a broad range of other proteins that are engaged in various molecular pathways such as ubiquitination, methylation, cell cycle control, gametogenesis, embryo development and cell wall formation...
May 27, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28550687/tanshinone-suppresses-arecoline-induced-epithelial-mesenchymal-transition-in-oral-submucous-fibrosis-by-epigenetically-reactivating-the-p53-pathway
#11
Lian Zheng, Zhen-Jie Guan, Wen-Ting Pan, Tian-Fang Du, Yu-Jia Zhai, Jia Guo
Oral submucous fibrosis (OSF) induced by the chewing of areca nut has been considered as a precancerous lesion with a higher probability of developing oral squamous cell carcinoma. Tanshinone (TSN) is the main component extracted from Salvia miltiorrhiza, a traditional Chinese medicine, which was found to have diverse pharmacological effects such as anti-inflammatory and anti-tumor effects. In current study, we aim to identify inhibitory effects and the underlying mechanism of Tanshinone on OSF progress. We found that treatment of TSN inhibited arecoline-mediated proliferation of primary human oral mucosal fibroblasts, and reversed the promotive effects of arecoline on EMT process...
May 21, 2017: Oncology Research
https://www.readbyqxmd.com/read/28545974/development-of-5-hydroxypyrazole-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#12
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
#13
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/28498828/kdm1a-lsd1-regulates-the-differentiation-and-maintenance-of-spermatogonia-in-mice
#14
Dexter A Myrick, Michael A Christopher, Alyssa M Scott, Ashley K Simon, Paul G Donlin-Asp, William G Kelly, David J Katz
The proper regulation of spermatogenesis is crucial to ensure the continued production of sperm and fertility. Here, we investigated the function of the H3K4me2 demethylase KDM1A/LSD1 during spermatogenesis in developing and adult mice. Conditional deletion of Kdm1a in the testis just prior to birth leads to fewer spermatogonia and germ cell loss before 3 weeks of age. These results demonstrate that KDM1A is required for spermatogonial differentiation, as well as germ cell survival, in the developing testis...
2017: PloS One
https://www.readbyqxmd.com/read/28486922/an-overview-on-screening-methods-for-lysine-specific-demethylase-1-lsd1-inhibitors
#15
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/28481366/the-zinc-finger-transcriptional-factor-slug-transcriptionally-downregulates-er%C3%AE-by-recruiting-lysine-specific-demethylase-1-in-human-breast-cancer
#16
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/28476938/chromatin-organization-at-the-nuclear-periphery-as-revealed-by-image-analysis-of-structured-illumination-microscopy-data
#17
Jindřiška Fišerová, Michaela Efenberková, Tomáš Sieger, Miloslava Maninová, Jana Uhlířová, Pavel Hozák
Nuclear periphery (NP) plays substantial role in chromatin organization. Heterochromatin at the NP is intermitted with active chromatin surrounding nuclear pore complexes (NPCs), however, details of the peripheral chromatin organization are missing. To discern the distributions of epigenetic marks at the NP of HeLa nuclei, we used structured illumination microscopy combined with a new MATLAB software tool for an automatic NP and NPC detection, measurements of fluorescent intensity and statistical analysis of measured data...
May 5, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28461471/lsd1-prevents-age-programed-loss-of-beige-adipocytes
#18
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
#19
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/28446510/a-postprandial-fgf19-shp-lsd1-regulatory-axis%C3%A2-mediates-epigenetic-repression-of-hepatic%C3%A2-autophagy
#20
Sangwon Byun, Young-Chae Kim, Yang Zhang, Bo Kong, Grace Guo, Junichi Sadoshima, Jian Ma, Byron Kemper, Jongsook Kim Kemper
Lysosome-mediated autophagy is essential for cellular survival and homeostasis upon nutrient deprivation, but is repressed after feeding. Despite the emerging importance of transcriptional regulation of autophagy by nutrient-sensing factors, the role for epigenetic control is largely unexplored. Here, we show that Small Heterodimer Partner (SHP) mediates postprandial epigenetic repression of hepatic autophagy by recruiting histone demethylase LSD1 in response to a late fed-state hormone, FGF19 (hFGF19, mFGF15)...
June 14, 2017: EMBO Journal
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