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https://www.readbyqxmd.com/read/27903753/a-novel-lsd1-inhibitor-t-3775440-disrupts-gfi1b-containing-complex-leading-to-transdifferentiation-and-impaired-growth-of-aml-cells
#1
Yoshinori Ishikawa, Kanae Gamo, Masato Yabuki, Shinji Takagi, Kosei Toyoshima, Kazuhide Nakayama, Akiko Nakayama, Megumi Morimoto, Hitoshi Miyashita, Ryo Dairiki, Yukiko Hikichi, Naoki Tomita, Daisuke Tomita, Shinichi Imamura, Misa Iwatani, Yusuke Kamada, Satoru Matsumoto, Ryujiro Hara, Toshiyuki Nomura, Ken Tsuchida, Kazuhide Nakamura
Dysregulation of the histone demethylase LSD1, also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here we describe the anti-leukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroleukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27893719/novel-kdm1a-inhibitors-induce-differentiation-and-apoptosis-of-glioma-stem-cells-via-unfolded-protein-response-pathway
#2
G R Sareddy, S Viswanadhapalli, P Surapaneni, T Suzuki, A Brenner, R K Vadlamudi
Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27879268/transcriptional-selectivity-of-epigenetic-therapy-in-cancer
#3
Takahiro Sato, Matteo Cesaroni, Woonbok Chung, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J Issa
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation and ChIP-seq analyses the epigenetic response of a set of colon, breast and leukemia cancer cell lines to small molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343)...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27879032/altered-expression-of-brg1-and-histone-demethylases-and-aberrant-h3k4-methylation-in-less-developmentally-competent-embryos-at-the-time-of-embryonic-genome-activation
#4
W G Glanzner, A Wachter, A R S Coutinho, M S Albornoz, R Duggavathi, P B D Gonçalves, V Bordignon
Epigenetics is a fundamental regulator underlying many biological functions, such as development and cell differentiation. Epigenetic modifications affect key chromatin regulation, including transcription and DNA repair, which are critical for normal embryo development. In this study, we profiled the expression of epigenetic modifiers and patterns of epigenetic changes in porcine embryos around the period of embryonic genome activation (EGA). We observed that Brahma-related gene 1 (BRG1) and Lysine demethylase 1A (KDM1A), which can alter the methylation status of lysine 4 in histone 3 (H3K4), localize to the nucleus at Days 3-4 of development...
November 23, 2016: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/27769034/design-synthesis-and-biological-evaluation-of-1-2-4-triazolo-1-5-a-pyrimidines-as-potent-lysine-specific-demethylase-1-lsd1-kdm1a-inhibitors
#5
Shuai Wang, Li-Jie Zhao, Yi-Chao Zheng, Dan-Dan Shen, Er-Fei Miao, Xue-Peng Qiao, Li-Juan Zhao, Ying Liu, Ruilei Huang, Bin Yu, Hong-Min Liu
A new series of [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 inhibitors were designed, synthesized, and further evaluated for their cytotoxicity against MGC-803, EC109, A549 and PC-9 cells as well as the ability of inhibiting LSD1. Some of these compounds showed potent inhibition toward LSD1 and selectively inhibited growth of A549 and PC-9 cells. Compound 6l potently inhibited growth of PC-9 cells (IC50 = 0.59 μM), about 4-fold more potent than 5-FU. Further SARs studies led to the identification of compounds 6l-m, which had good growth inhibition against all the tested cancer cell lines and were much more potent than 5-FU and GSK2879552...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27645313/class-i-lysine-deacetylases-promote-glucocorticoid-induced-transcriptional-repression-through-functional-interaction-with-lsd1
#6
Nina M Patrick, Chanel A Griggs, Ali L Icenogle, Maryam M Gilpatrick, Vineela Kadiyala, Rosa Jaime-Frias, Catharine L Smith
Small molecule inhibitors of lysine deacetylases (KDACs) are approved for clinical use in treatment of several diseases. Nuclear receptors, such as the glucocorticoid receptor (GR) use lysine acetyltransferases (KATs or HATs) and KDACs to regulate transcription through acetylation and deacetylation of protein targets such as histones. Previously we have shown that KDAC1 activity facilitates GR-activated transcription at about half of all cellular target genes. In the current study we examine the role of Class I KDACs in glucocorticoid-mediated repression of gene expression...
September 16, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27634040/activity-dependent-regulation-of-histone-lysine-demethylase-kdm1a-by-a-putative-thiol-disulfide-switch
#7
Emily L Ricq, Jacob M Hooker, Stephen J Haggarty
Lysine demethylation of proteins such as histones is catalyzed by several classes of enzymes, including the FAD-dependent amine oxidases KDM1A/B. The KDM1 family is homologous to the mitochondrial monoamine oxidases MAO-A/B and produces hydrogen peroxide in the nucleus as a byproduct of demethylation. Here, we show KDM1A is highly thiol-reactive in vitro and in cellular models. Enzyme activity is potently and reversibly inhibited by the drug disulfiram and by hydrogen peroxide. Hydrogen peroxide produced by KDM1A catalysis reduces thiol labeling and inactivates demethylase activity over time...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27626075/polymyxins-and-quinazolines-are-lsd1-kdm1a-inhibitors-with-unusual-structural-features
#8
Valentina Speranzini, Dante Rotili, Giuseppe Ciossani, Simona Pilotto, Biagina Marrocco, Mariantonietta Forgione, Alessia Lucidi, Federico Forneris, Parinaz Mehdipour, Sameer Velankar, Antonello Mai, Andrea Mattevi
Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center...
September 2016: Science Advances
https://www.readbyqxmd.com/read/27501329/nuclear-gsk3%C3%AE-promotes-tumorigenesis-by-phosphorylating-kdm1a-and-inducing-its-deubiquitylation-by-usp22
#9
Aidong Zhou, Kangyu Lin, Sicong Zhang, Yaohui Chen, Nu Zhang, Jianfei Xue, Zhongyong Wang, Kenneth D Aldape, Keping Xie, James R Woodgett, Suyun Huang
Emerging evidence has shown that GSK3β plays oncogenic roles in multiple tumour types; however, the underlying mechanisms remain largely unknown. Here, we show that nuclear GSK3β is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during tumorigenesis. GSK3β phosphorylates KDM1A Ser683 upon priming phosphorylation of KDM1A Ser687 by CK1α. Phosphorylation of KDM1A induces its binding with and deubiquitylation by USP22, leading to KDM1A stabilization...
September 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27479862/lsd1-biologic-roles-and-therapeutic-targeting
#10
Alba Maiques-Diaz, Tim Cp Somervaille
LSD1 (KDM1A; BHC110; AOF2) was the first protein reported to exhibit histone demethylase activity and has since been shown to have multiple essential roles in mammalian biology. Given its enzymatic activity and its high-level expression in many human malignancies, a significant recent focus has been the development of pharmacologic inhibitors. Here we summarize structural and biochemical knowledge of this important epigenetic regulator, with a particular emphasis on the functional and preclinical studies in oncology that have provided justification for the evaluation of tranylcypromine derivative LSD1 inhibitors in early phase clinical trials...
August 2016: Epigenomics
https://www.readbyqxmd.com/read/27470128/the-growing-structural-and-functional-complexity-of-the-lsd1-kdm1a-histone-demethylase
#11
Chiara Marabelli, Biagina Marrocco, Andrea Mattevi
LSD1 was the first discovered histone demethylase. Using a flavin-dependent oxidative mechanism, LSD1 demethylates the N-terminal tail of histone H3 in the context of a variety of developmental processes. This functional complexity involves the association with nuclear factors and non-coding RNAs. A number of exciting studies are uncovering the bases of these specific and diverse molecular interactions, which occur both at catalytic and non-catalytic regions of the enzyme. Alternative splicing and post-translation modifications represent further layers for modulating this complex molecular network...
July 25, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27449289/the-interplay-between-the-lysine-demethylase-kdm1a-and-dna-methyltransferases-in-cancer-cells-is-cell-cycle-dependent
#12
Carmen Brenner, Judith Luciani, Martin Bizet, Matladi Ndlovu, Eleonore Josseaux, Sarah Dedeurwaerder, Emilie Calonne, Pascale Putmans, Pierre-Francois Cartron, Matthieu Defrance, François Fuks, Rachel Deplus
DNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells. Previous work on ES cells has shown that the lysine demethylase KDM1A binds to DNMT1, thereby affecting DNA methylation. In cancer cells, the occurrence of this interaction has not been explored...
July 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27447975/molecular-mechanisms-of-olig2-transcription-factor-in-brain-cancer
#13
Igor F Tsigelny, Valentina L Kouznetsova, Nathan Lian, Santosh Kesari
Oligodendrocyte lineage transcription factor 2 (OLIG2) plays a pivotal role in glioma development. Here we conducted a comprehensive study of the critical gene regulatory networks involving OLIG2. These include the networks responsible for OLIG2 expression, its translocation to nucleus, cell cycle, epigenetic regulation, and Rho-pathway interactions. We described positive feedback loops including OLIG2: loops of epigenetic regulation and loops involving receptor tyrosine kinases. These loops may be responsible for the prolonged oncogenic activity of OLIG2...
July 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27400875/transcriptome-sequencing-reveals-that-lps-triggered-transcriptional-responses-in-established-microglia-bv2-cell-lines-are-poorly-representative-of-primary-microglia
#14
Amitabh Das, Sun Hwa Kim, Sarder Arifuzzaman, Taeho Yoon, Jin Choul Chai, Young Seek Lee, Kyoung Sun Park, Kyoung Hwa Jung, Young Gyu Chai
BACKGROUND: Microglia are resident myeloid cells in the CNS that are activated by infection, neuronal injury, and inflammation. Established BV2 microglial cell lines have been the primary in vitro models used to study neuroinflammation for more than a decade because they reduce the requirement of continuously maintaining cell preparations and animal experimentation models. However, doubt has recently been raised regarding the value of BV2 cell lines as a model system. METHODS: We used triplicate RNA sequencing (RNA-seq) to investigate the molecular signature of primary and BV2 microglial cell lines using two transcriptomic techniques: global transcriptomic biological triplicate RNA-seq and quantitative real-time PCR...
2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27375009/histone-demethylase-lsd1-controls-the-phenotypic-plasticity-of-cancer-cells
#15
REVIEW
Shinjiro Hino, Kensaku Kohrogi, Mitsuyoshi Nakao
Epigenetic mechanisms underlie the phenotypic plasticity of cells, while aberrant epigenetic regulation through genetic mutations and/or misregulated expression of epigenetic factors leads to aberrant cell fate determination, which provides a foundation for oncogenic transformation. Lysine-specific demethylase-1 (LSD1, KDM1A) removes methyl groups from methylated proteins, including histone H3, and is frequently overexpressed in various types of solid tumors and hematopoietic neoplasms. While LSD1 is involved in a wide variety of normal physiological processes, including stem cell maintenance and differentiation, it is also a key player in oncogenic processes, including compromised differentiation, enhanced cell motility and metabolic reprogramming...
September 2016: Cancer Science
https://www.readbyqxmd.com/read/27372756/expression-purification-and-biochemical-analysis-of-the-lsd1-kdm1a-histone-demethylase
#16
B Laurent, Y Shi
Posttranslational modifications (PTMs) of histones play important roles in the regulation of chromatin architecture and gene transcription. A decade ago, it was still believed that methyl groups could not be removed from histones, until the first histone demethylase LSD1 (lysine-specific demethylase 1; also known as KDM1A) was identified. This discovery initiated an era in the understanding of chromatin dynamic regulation by active histone demethylation. Since then, the repertoire of histone demethylases has expanded, and our understanding of the molecular mechanisms, structures, and macromolecular complexes of the demethylases has grown significantly...
2016: Methods in Enzymology
https://www.readbyqxmd.com/read/27349498/reversible-lysine-specific-demethylase-1-antagonist-hci-2509-inhibits-growth-and-decreases-c-myc-in-castration-and-docetaxel-resistant-prostate-cancer-cells
#17
S Gupta, A Weston, J Bearrs, T Thode, A Neiss, R Soldi, S Sharma
BACKGROUND: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer. METHODS: Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509...
June 28, 2016: Prostate Cancer and Prostatic Diseases
https://www.readbyqxmd.com/read/27094131/lsd1-kdm1a-mutations-associated-to-a-newly-described-form-of-intellectual-disability-impair-demethylase-activity-and-binding-to-transcription-factors
#18
Simona Pilotto, Valentina Speranzini, Chiara Marabelli, Francesco Rusconi, Emanuela Toffolo, Barbara Grillo, Elena Battaglioli, Andrea Mattevi
Genetic diseases often lead to rare and severe syndromes and the identification of the genetic and protein alterations responsible for the pathogenesis is essential to understand both the physiological and pathological role of the gene product. Recently, de novo variants have been mapped on the gene encoding for the lysine-specific histone demethylase 1 (LSD1)/lysine(K)-specific histone demethylase 1A in three patients characterized by a new genetic disorder. We have analyzed the effects of these pathological mutations on the structure, stability and activity of LSD1 using both in vitro and cellular approaches...
April 19, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27059868/inhibition-of-lysine-specific-demethylase-1-lsd1-kdm1a-promotes-the-adipogenic-differentiation-of-hescs-through-h3k4-methylation
#19
Yujing Xiong, Enyin Wang, Yan Huang, Xiaoyi Guo, Yiping Yu, Qingyun Du, Xiaoyan Ding, Yingpu Sun
Given their totipotency, human embryonic stem cells (hESCs) can differentiate into all types of cells, including adipocytes, and provide an excellent research model for studying diseases associated with the metabolism of adipocytes, such as obesity and diabetes mellitus. Epigenetic regulation, including DNA methylation and histone modification, plays an essential role in the development and differentiation of hESCs. Lysine-specific demethylase 1 (LSD1), a well-characterized histone-modifying enzyme, demethylates dimethylated histone H3 lysine 4 (H3K4) through a flavin adenine dinucleotide (FAD)-dependent oxidative reaction...
June 2016: Stem Cell Reviews
https://www.readbyqxmd.com/read/27058897/kdm1a-promotes-tumor-cell-invasion-by-silencing-timp3-in-non-small-cell-lung-cancer-cells
#20
Lingzhi Kong, Peng Zhang, Wang Li, Yan Yang, Ye Tian, Xujun Wang, Sujun Chen, Yuxin Yang, Tianhao Huang, Tian Zhao, Liang Tang, Bo Su, Fei Li, X Shirley Liu, Fan Zhang
Epigenetic regulation plays an important role in tumor metastasis. KDM1A is a histone demethylase specific for H3K4me2/me1 demethylation, and has been found to be overexpressed in many cancers, including non-small cell lung cancer (NSCLC). However, the role of KDM1A in lung cancer remains unclear. Here, we show that KDM1A promotes cancer metastasis in NSCLC cells by repressing TIMP3 (tissue inhibitor of metalloproteinase 3) expression. Consistently with this, overexpression of TIMP3 inhibited MMP2 expression and JNK phosphorylation, both of which are known to be important for cell invasion and migration...
May 10, 2016: Oncotarget
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