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Lysine specific demethylase

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https://www.readbyqxmd.com/read/28230862/inactivation-of-lsd1-triggers-senescence-in-trophoblast-stem-cells-by-induction-of-sirt4
#1
Josefina Castex, Dominica Willmann, Toufike Kanouni, Laura Arrigoni, Yan Li, Marcel Friedrich, Michael Schleicher, Simon Wöhrle, Mark Pearson, Norbert Kraut, Michaël Méret, Thomas Manke, Eric Metzger, Roland Schüle, Thomas Günther
Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function...
February 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28223039/oncogene-lsd1-is-epigenetically-suppressed-by-mir-137-overexpression-in-human-non-small-cell-lung-cancer
#2
Xin Zhang, Xiujuan Zhang, Bo Yu, Rongpeng Hu, Lanxiang Hao
PURPOSE: We examined the epigenetic regulation of microRNA-137 (miR-137) on lysine-specific demethylase 1 (KDM1A, or LSD1) induced oncogenic effects in NSCLC. METHODS: NSCLC cell lines, A549 and H460 cells were transfected with a mammalian LSD1 overexpression plasmid. It's effects on endogenous KDM1A gene and LSD1 protein expressions were examined by qRT-PCR and western blot assays. NSCLC proliferation and migration were also examined by MTT proliferation and wound-scratch assays, respectively...
February 18, 2017: Biochimie
https://www.readbyqxmd.com/read/28219005/a-rhodium-iii-based-inhibitor-of-lysine-specific-histone-demethylase-1-as-an-epigenetic-modulator-in-prostate-cancer-cells
#3
Chao Yang, Wanhe Wang, Jiaxin Liang, Guodong Li, Kasipandi Vellaisamy, Chun-Yuen Wong, Dik-Lung Ma, Chung-Hang Leung
We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells, and enhanced the amplification of p21, FOXA2 and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7 and MAO activities, and also showed anti-proliferative activity towards human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28212444/sumo-modification-of-a-heterochromatin-histone-demethylase-jmjd2a-enables-viral-gene-transactivation-and-viral-replication
#4
Wan-Shan Yang, Mel Campbell, Pei-Ching Chang
Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi's sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation...
February 17, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28210006/a-novel-lsd1-inhibitor-ncd38-ameliorates-mds-related-leukemia-with-complex-karyotype-by-attenuating-leukemia-programs-via-activating-super-enhancers
#5
N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDS) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells...
February 17, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28188179/new-insights-into-the-role-of-jmjd3-and-utx-in-axial-skeletal-formation-in-mice
#6
Chie Naruse, Shinwa Shibata, Masaru Tamura, Takayuki Kawaguchi, Kanae Abe, Kazushi Sugihara, Tomoaki Kato, Takumi Nishiuchi, Shigeharu Wakana, Masahito Ikawa, Masahide Asano
Jmjd3 and Utx are demethylases specific for lysine 27 of histone H3. Previous reports indicate that Jmjd3 is essential for differentiation of various cell types, such as macrophages and epidermal cells in mice, whereas Utx is involved in cancer and developmental diseases in humans and mice as well as Hox regulation in zebrafish and nematodes. Here, we report that Jmjd3, but not Utx, is involved in axial skeletal formation in mice. A Jmjd3 mutant embryo (Jmjd3(Δ18/Δ18)), but not a catalytically inactive Utx truncation mutant (Utx(-/y)), showed anterior homeotic transformation...
February 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28186755/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-1-high-throughput-screening-and-preliminary-exploration
#7
Luca Sartori, Ciro Mercurio, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Manuela Villa, Stefania Vultaggio, Oronza A Botrugno, Paola Dessanti, Saverio Minucci, Elisa Zagarrí, Daniele Carettoni, Lucia Iuzzolino, Mario Varasi, Paola Vianello
Lysine specific demethylase 1 KDM1A (LSD1) is one regulator of histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying 4 chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28158205/structure-activity-relationship-and-modeling-studies-of-inhibitors-of-lysine-specific-demethylase-1
#8
Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B...
2017: PloS One
https://www.readbyqxmd.com/read/28152483/lsd1-collaborates-with-ezh2-to-regulate-expression-of-interferon-stimulated-genes
#9
Yue Jin, Bo Huo, Xueqi Fu, Tian Hao, Yu Zhang, Yidi Guo, Xin Hu
Histone methylation is a complicate and dynamic epigenetic modification that regulates gene transcription, chromosomal structure and cell differentiation. Here, we discovered the interaction between the H3K4 demethylase, lysine specific demethylase 1 (LSD1, an important component of CoREST repressor complex) and the H3K27 methyltransferase, enhancer of zeste homolog 2 (EZH2, an essential component of PRC2). Immuno-precipitation and GST-pull down assay were performed to observe the interaction between the proteins...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28144654/the-small-molecule-jib-04-disrupts-o2-binding-in-the-fe-dependent-histone-demethylase-kdm4a-jmjd2a
#10
Barbara Cascella, Soon Goo Lee, Sukrit Singh, Joseph M Jez, Liviu M Mirica
JIB-04, a specific inhibitor of the O2-activating, Fe-dependent histone lysine demethylases, is revealed to disrupt the binding of O2 in KDM4A/JMJD2A through a continuous O2-consumption assay, X-ray crystal structure data, and molecular docking.
February 9, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28132772/profiling-of-human-epigenetic-regulators-using-a-semi-automated-real-time-qpcr-platform-validated-by-next-generation-sequencing
#11
Amel Dudakovic, Martina Gluscevic, Christopher R Paradise, Halil Dudakovic, Farzaneh Khani, Roman Thaler, Farah S Ahmed, Xiaodong Li, Allan B Dietz, Gary S Stein, Martin A Montecino, David R Deyle, Jennifer J Westendorf, Andre J van Wijnen
Epigenetic mechanisms control phenotypic commitment of mesenchymal stromal/stem cells (MSCs) into osteogenic, chondrogenic or adipogenic lineages. To investigate enzymes and chromatin binding proteins controlling the epigenome, we developed a hybrid expression screening strategy that combines semi-automated real-time qPCR (RT-qPCR), next generation RNA sequencing (RNA-seq), and a novel data management application (FileMerge). This strategy was used to interrogate expression of a large cohort (n>300) of human epigenetic regulators (EpiRegs) that generate, interpret and/or edit the histone code...
April 20, 2017: Gene
https://www.readbyqxmd.com/read/28123630/set-and-mynd-domain-containing-protein-3-in-cancer
#12
REVIEW
Lei Huang, A-Man Xu
Lysine methylation plays a vital role in histone modification. Deregulations of lysine methyltransferases and demethylases have been frequently observed in human cancers. The SET and MYND domain containing protein 3 (SMYD3) is a novel histone lysine methyltransferase and it functions by regulating chromatin during the development of myocardial and skeletal muscle. It has been recently unveiled to play significant roles in human cancer genesis and progression via regulating various key cancer-associated genes and pathways and promoting cell proliferation and migration...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28121627/identification-of-downstream-metastasis-associated-target-genes-regulated-by-lsd1-in-colon-cancer-cells
#13
Jiang Chen, Jie Ding, Ziwei Wang, Jian Zhu, Xuejian Wang, Jiyi Du
PURPOSE: This study aims to identify downstream target genes regulated by lysine-specific demethylase 1 (LSD1) in colon cancer cells and investigate the molecular mechanisms of LSD1 influencing invasion and metastasis of colon cancer. METHOD: We obtained the expression changes of downstream target genes regulated by small-interfering RNA-LSD1 and LSD1-overexpression via gene expression profiling in two human colon cancer cell lines. An Affymetrix Human Transcriptome Array 2...
January 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28112720/long-noncoding-rna-hoxa-as2-represses-p21-and-klf2-expression-transcription-by-binding-with-ezh2-lsd1-in-colorectal-cancer
#14
J Ding, M Xie, Y Lian, Y Zhu, P Peng, J Wang, L Wang, K Wang
Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer (CRC) are not known...
January 23, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28098854/lsd1-sustains-estrogen-driven-endometrial-carcinoma-cell-proliferation-through-the-pi3k-akt-pathway-via-di-demethylating-h3k9-of-cyclin%C3%A2-d1
#15
Chunqin Chen, Yanan Wang, Shiyu Wang, Yuan Liu, Jiawen Zhang, Yuyao Xu, Zhenbo Zhang, Wei Bao, Sufang Wu
A recent study reported that histone lysine specific demethylase 1 (LSD1, KDM1A) is overexpressed in endometrioid endometrial carcinoma (EEC) and associated with tumor progression as well as poor prognosis. However, the physiological function and mechanism of LSD1 in endometrial cancer (EC) remains largely unknown. In this study, we demonstrate that β-estradiol (E2) treatment increased LSD1 expression via the GPR30/PI3K/AKT pathway in endometrial cancer cells. Both siGPR30 and the PI3K inhibitor LY294002 block this effect...
March 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28088469/estrogen-induced-expression-of-tissue-factor-pathway-inhibitor-2-in-mcf7-cells-involves-lysine-specific-demethylase-1
#16
Marianne S Andresen, Huda Omar Ali, Christiane Filion Myklebust, Per Morten Sandset, Benedicte Stavik, Nina Iversen, Grethe Skretting
Hormone-sensitive cancers can be influenced by estrogens, a process usually mediated through the estrogen receptor (ER). Tissue factor pathway inhibitor type 2 (TFPI-2) is a Kunitz-type serine protease inhibitor involved in regulating the extracellular matrix. The present study demonstrates that the expression of TFPI-2 can be induced by estrogens. Breast cancer data from GOBO displayed increased levels of TFPI-2 and increased survival in patients with ERα+ tumors. Treatment of MCF7 cells (ERα+) with 17β-estradiol (E2) or 17α-ethinyl estradiol (EE2) increased TFPI-2 mRNA and protein levels...
January 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28069602/oncogenic-zeb2-activation-drives-sensitivity-towards-kdm1a-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#17
Steven Goossens, Sofie Peirs, Wouter Van Loocke, Jueqiong Wang, Mina Takawy, Filip Matthijssens, Stefan E Sonderegger, Katharina Haigh, Thao Nguyen, Niels Vandamme, Magdaline Costa, Catherine Carmichael, Filip Van Nieuwerburgh, Dieter Deforce, Oded Kleifeld, David J Curtis, Geert Berx, Pieter Van Vlierberghe, Jody J Haigh
Elevated expression of the Zinc finger E-box binding homeobox transcription factor-2 (ZEB2) is correlated with poor prognosis and patient outcome in a variety of human cancer subtypes. Using a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventional chemotherapy. Here, we identified the Lysine-specific demethylase KDM1A as a novel interaction partner of ZEB2 and demonstrated that mouse and human T-ALLs with increased ZEB2 levels critically depend on KDM1A activity for survival...
January 9, 2017: Blood
https://www.readbyqxmd.com/read/28065500/activation-of-lysine-specific-demethylase-1-inhibitor-peptide-by-redox-controlled-cleavage-of-a-traceless-linker
#18
Yuichi Amano, Naoki Umezawa, Shin Sato, Hisami Watanabe, Takashi Umehara, Tsunehiko Higuchi
We have previously employed cyclization of a linear peptide as a strategy to modulate peptide function and properties, but cleavage to regenerate the linear peptide left parts of the linker structure on the peptide, interfering with its activity. Here, we focused on cyclization of a linear peptide via a "traceless" disulfide-based linkage that would be cleaved and completely removed in a reducing environment, regenerating the original linear peptide without any linker-related structure. Thus, the linker would serve as a redox switch that would be activated in the intracellular environment...
December 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28049654/histone-lysine-demethylase-inhibitors
#19
REVIEW
Ashwini Jambhekar, Jamie N Anastas, Yang Shi
The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors...
January 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28041878/epigenetic-modifiers-facilitate-induction-and-pluripotency-of-porcine-ipscs
#20
Jian Mao, Qian Zhang, Wei Deng, Hua Wang, Kai Liu, Haifeng Fu, Qiang Zhao, Xumin Wang, Lin Liu
Inadequate silencing of exogenous genes represents a major obstacle to complete epigenetic reprogramming of porcine-induced pluripotent stem cells (piPSCs) by conventional pluripotency transcription factors (OSKM). We tested the hypothesis that epigenetic modification by active DNA or histone demethylation or by inhibition of histone deacetylase would enhance reprogramming and exogenous gene silencing in piPSCs. piPSCs induced by OSKM in combination with epigenetic factors, specifically Ten-Eleven Translocation (Tet1 or Tet3) or lysine (K)-specific demethylase 3A (Kdm3a), expressed higher levels of Rex1 and other genes representing naive state and exhibited more open chromatin status, compared with those of OSKM controls...
January 10, 2017: Stem Cell Reports
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