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Lysine specific demethylase

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https://www.readbyqxmd.com/read/29765516/selective-dissociation-between-lsd1-and-gfi1b-by-a-lsd1-inhibitor-ncd38-induces-the-activation-of-erg-super-enhancer-in-erythroleukemia-cells
#1
Ryusuke Yamamoto, Masahiro Kawahara, Shinji Ito, Junko Satoh, Goichi Tatsumi, Masakatsu Hishizawa, Takayoshi Suzuki, Akira Andoh
Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29749504/lsd1-negatively-regulates-autophagy-through-the-mtor-signaling-pathway-in-ovarian-cancer-cells
#2
Ye Wei, Tiantian Han, Ranran Wang, Jing Wei, Ke Peng, Qiong Lin, Genbao Shao
Lysine-specific demethylase 1 (LSD1) plays a key role in cell proliferation, differentiation and carcinogenesis. In the present study we revealed that LSD1 functioned as an autophagy suppressor in ovarian cancer HO8910 cells. Pharmacological inhibition or genetic knockdown of LSD1 resulted in the elevation of the LC3‑II protein, enhancement of autophagosomal formation and stimulation of the autophagic flux. In addition, knockdown of LSD1 further promoted the serum starvation- and rapamycin-induced autophagy...
May 10, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29741645/lsd1-coordinates-with-the-sin3a-hdac-complex-and-maintains-sensitivity-to-chemotherapy-in-breast-cancer
#3
Yang Yang, Wei Huang, Rongfang Qiu, Ruiqiong Liu, Yi Zeng, Jie Gao, Yu Zheng, Yongqiang Hou, Shuang Wang, Wenqian Yu, Shuai Leng, Dandan Feng, Yan Wang
Lysine-specific demethylase 1 (LSD1) was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex...
May 7, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29734782/design-synthesis-and-in-vitro-evaluation-of-novel-histone-h3-peptide-based-lsd1-inactivators-incorporating-%C3%AE-%C3%AE-disubstituted-amino-acids-with-%C3%AE-turn-inducing-structures
#4
Yosuke Ota, Taeko Kakizawa, Yukihiro Itoh, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1...
May 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29725259/expanding-the-oro-dental-and-mutational-spectra-of-kabuki-syndrome-and-expression-of-kmt2d-and-kdm6a-in-human-tooth-germs
#5
Thantrira Porntaveetus, Mushriq F Abid, Thanakorn Theerapanon, Chalurmpon Srichomthong, Atsushi Ohazama, Katsushige Kawasaki, Maiko Kawasaki, Kanya Suphapeetiporn, Paul T Sharpe, Vorasuk Shotelersuk
Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of KMT2D (histone-lysine N-methyltransferase 2D) or KDM6A (lysine-specific demethylase 6A) genes in tooth development have not been well defined. Here, we report seven unrelated Thai patients with Kabuki syndrome having congenital absence of teeth, malocclusion, high-arched palate, micrognathia, and deviated tooth shape and size...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29707403/histone-demethylase-lsd1-regulates-bone-mass-by-controlling-wnt7b-and-bmp2-signaling-in-osteoblasts
#6
Jun Sun, Joerg Ermann, Ningning Niu, Guang Yan, Yang Yang, Yujiang Shi, Weiguo Zou
Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2...
2018: Bone Research
https://www.readbyqxmd.com/read/29691138/targeting-lysine-specific-demethylase-4a-kdm4a-tandem-tudor-domain-a-fragment-based-approach
#7
Anup K Upadhyay, Russell A Judge, Leiming Li, Ron Pithawalla, Justin Simanis, Pierre M Bodelle, Violeta L Marin, Rodger F Henry, Andrew M Petros, Chaohong Sun
The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays...
April 19, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29683067/lysine-specific-demethylase-2a-expression-is-associated-with-cell-growth-and-cyclin-d1-expression-in-colorectal-adenocarcinoma
#8
Lin-Lin Cao, Changzheng Du, Hangqi Liu, Lin Pei, Li Qin, Mei Jia, Hui Wang
OBJECTIVE: Lysine-specific demethylase 2A (KDM2A), a specific H3K36me1/2 demethylase, has been reported to be closely associated with several types of cancer. In this study, we aimed to investigate the expression and function of KDM2A in colorectal adenocarcinoma. METHODS: A total of 215 colorectal adenocarcinoma specimens were collected, and then subjected to immunohistochemistry assay to evaluate the expression levels of KDM2A, cyclin D1 and other proteins in colorectal adenocarcinoma tissues...
April 1, 2018: International Journal of Biological Markers
https://www.readbyqxmd.com/read/29642935/sp1-induced-upregulation-of-lncrna-spry4-it1-exerts-oncogenic-properties-by-scaffolding-ezh2-lsd1-dnmt1-and-sponging-mir-101-3p-in-cholangiocarcinoma
#9
Yi Xu, Yue Yao, Xingming Jiang, Xiangyu Zhong, Zhidong Wang, Chunlong Li, Pengcheng Kang, Kaiming Leng, Daolin Ji, Zhenglong Li, Lining Huang, Wei Qin, Yunfu Cui
BACKGROUND: Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) behave as a novel class of transcription products during multiple cancer processes. However, the mechanisms responsible for their alteration in cholangiocarcinoma (CCA) are not fully understood. METHODS: The expression of SPRY4-IT1 in CCA tissues and cell lines was determined by RT-qPCR, and the association between SPRY4-IT1 transcription and clinicopathologic features was analyzed...
April 11, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29618057/lsd1-mediates-metabolic-reprogramming-by-glucocorticoids-during-myogenic-differentiation
#10
Kotaro Anan, Shinjiro Hino, Noriaki Shimizu, Akihisa Sakamoto, Katsuya Nagaoka, Ryuta Takase, Kensaku Kohrogi, Hirotaka Araki, Yuko Hino, Shingo Usuki, Shinya Oki, Hirotoshi Tanaka, Kimitoshi Nakamura, Fumio Endo, Mitsuyoshi Nakao
The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids. By using transcriptomic and epigenomic approaches, we revealed that LSD1 bound to oxidative metabolism and slow-twitch myosin genes, and repressed their expression...
March 29, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29610759/molecular-signature-of-the-imprintosome-complex-at-the-mating-type-locus-in-fission-yeast
#11
Célia Raimondi, Bernd Jagla, Caroline Proux, Hervé Waxin, Serge Gangloff, Benoit Arcangioli
Genetic and molecular studies have indicated that an epigenetic imprint at mat1 , the sexual locus of fission yeast, initiates mating type switching. The polar DNA replication of mat1 generates an imprint on the Watson strand. The process by which the imprint is formed and maintained through the cell cycle remains unclear. To understand better the mechanism of imprint formation and stability, we characterized the recruitment of early players of mating type switching at the mat1 region. We found that the switch activating protein 1 (Sap1) is preferentially recruited inside the mat1M allele on a sequence ( SS13 ) that enhances the imprint...
January 16, 2018: Microbial Cell
https://www.readbyqxmd.com/read/29602065/targeting-histone-demethylases-kdm5a-and-kdm5b-in-aml-cancer-cells-a-comparative-view
#12
Gelareh Shokri, Shaghayegh Doudi, Mehrnoosh Fathi-Roudsari, Fatemeh Kouhkan, Mohammad-Hossein Sanati
Epigenetic modifications play an important role in initiation and progression of cancers including acute myeloid leukemia. Among different epigenetic modifiers, lysine specific demethylases have been noticed as potential therapeutic targets. KDM5 family of histone demethylases which removes methyl marks from lysine residues of H3, are frequently found in the promoter region of transcriptionally active genes resulting in repression of expression. Here we have compared the effects of KDM5A and KDM5B downregulation on HL-60 cell line behavior...
May 2018: Leukemia Research
https://www.readbyqxmd.com/read/29594337/therapeutic-potential-of-gsk-j4-a-histone-demethylase-kdm6b-jmjd3-inhibitor-for-acute-myeloid-leukemia
#13
Yunan Li, Mingying Zhang, Mengyao Sheng, Peng Zhang, Zizhen Chen, Wen Xing, Jie Bai, Tao Cheng, Feng-Chun Yang, Yuan Zhou
PURPOSE: Acute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML. METHODS: A KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo...
March 28, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29593255/stress-induced-phosphoprotein-1-acts-as-a-scaffold-protein-for-glycogen-synthase-kinase-3-beta-mediated-phosphorylation-of-lysine-specific-demethylase-1
#14
Chia-Lung Tsai, An-Shine Chao, Shih-Ming Jung, Chiao-Yun Lin, Angel Chao, Tzu-Hao Wang
Stress-induced phosphoprotein 1 (STIP1)-a co-chaperone of heat shock proteins-promotes cell proliferation and may act as an oncogenic factor. Similarly, glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of lysine-specific demethylase 1 (LSD1)-an epigenetic regulator-can contribute to the development of an aggressive cell phenotype. Owing to their ability to tether different molecules into functional complexes, scaffold proteins have a key role in the regulation of different signaling pathways in tumorigenesis...
March 29, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29581250/lsd1-activates-a-lethal-prostate-cancer-gene-network-independently-of-its-demethylase-function
#15
Archana Sehrawat, Lina Gao, Yuliang Wang, Armand Bankhead, Shannon K McWeeney, Carly J King, Jacob Schwartzman, Joshua Urrutia, William H Bisson, Daniel J Coleman, Sunil K Joshi, Dae-Hwan Kim, David A Sampson, Sheila Weinmann, Bhaskar V S Kallakury, Deborah L Berry, Reina Haque, Stephen K Van Den Eeden, Sunil Sharma, Jared Bearss, Tomasz M Beer, George V Thomas, Laura M Heiser, Joshi J Alumkal
Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR...
May 1, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29559475/germline-lysine-specific-demethylase-1-lsd1-kdm1a-mutations-confer-susceptibility-to-multiple-myeloma
#16
Xiaomu Wei, M Nieves Calvo-Vidal, Siwei Chen, Gang Wu, Maria V Revuelta, Jian Sun, Jinghui Zhang, Michael F Walsh, Kim E Nichols, Vijai Joseph, Carrie Snyder, Celine M Vachon, James D McKay, Shu-Ping Wang, David S Jayabalan, Lauren M Jacobs, Dina Becirovic, Rosalie G Waller, Mykyta Artomov, Agnes Viale, Jayeshkumar Patel, Jude Phillip, Selina Chen-Kiang, Karen Curtin, Mohamed Salama, Djordje Atanackovic, Ruben Niesvizky, Ola Landgren, Susan L Slager, Lucy A Godley, Jane Churpek, Judy E Garber, Kenneth C Anderson, Mark J Daly, Robert G Roeder, Charles Dumontet, Henry T Lynch, Charles G Mullighan, Nicola J Camp, Kenneth Offit, Robert J Klein, Haiyuan Yu, Leandro Cerchietti, Steven M Lipkin
Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29555846/pias%C3%AE-controls-stability-and-facilitates-sumo-2-conjugation-to-corest-family-of-transcriptional-corepressors
#17
Julián Esteban Sáez, Cristian Arredondo, Carlos Rivera, María Estela Andrés
CoREST family of transcriptional corepressors regulates gene expression and cell fate determination during development. CoREST corepressors recruit with different affinity the histone demethylase LSD1 (KDM1A) and the deacetylases HDAC1/2 to repress with variable strength the expression of target genes. CoREST protein levels are differentially regulated during cell fate decisions and in mature tissues. However, regulatory mechanisms of CoREST corepressors at the protein level have not been studied. Here, we report that CoREST (CoREST1, RCOR1) and its homologs CoREST2 (RCOR2) and CoREST3 (RCOR3) interact with PIASγ, a SUMO-E3 ligase...
March 19, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29542357/treating-donor-cells-with-2-pcpa-corrects-aberrant-histone-h3k4-dimethylation-and-improves-cloned-goat-embryo-development
#18
Tingchao Mao, Chengquan Han, Ruizhi Deng, Biao Wei, Peng Meng, Yan Luo, Yong Zhang
Epigenetic modifications extensively occur in mammalian embryonic development and cell differentiation process. They play an essential role in the reprogramming of nuclei during somatic cell nuclear transfer (SCNT) and subsequent in vitro embryonic development. Recently, SCNT embryos have been verified to contain a subnormal level of histone H3K4 dimethylation (H3K4me2) in contrast to in vitro fertilized embryos. This finding suggested that increasing H3K4me2 levels may ameliorate the aberrant development of cloned embryos...
March 15, 2018: Systems Biology in Reproductive Medicine
https://www.readbyqxmd.com/read/29534805/bioactivity-guided-cut-countercurrent-chromatography-for-isolation-of-lysine-specific-demethylase-1-inhibitors-from-scutellaria-baicalensis-georgi
#19
Chao Han, Shanshan Wang, Zhongrui Li, Chen Chen, Jiqin Hou, Dingqiao Xu, Ruizhi Wang, Yaolan Lin, Jianguang Luo, Lingyi Kong
Countercurrent chromatography (CCC) has gradually become a widely used method for preparative separation of bioactive natural molecules. These molecules generally contain distinct scaffolds and characteristics that cannot be readily isolated from plants. While one-dimensional CCC is typically used for the initial purification with insufficiently resolved peaks after locating bioactive components, two-dimensional (2D) or multi-dimensional CCC strategies are employed to improve the resolution of peaks. However, these methods usually present certain disadvantages, such as complicated procedures and increased time consumption, experimental costs, and equipment requirements...
August 3, 2018: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29533778/ory-1001-overcoming-the-differentiation-block-in-aml
#20
Prithviraj Bose, Marina Y Konopleva
In this issue of Cancer Cell, Maes and colleagues report in vitro and in vivo findings with ORY-1001-an oral, highly potent and selective covalent small-molecule inhibitor of lysine-specific demethylase 1 (LSD1)-in development for acute myeloid leukemia (AML), as well as correlative data from two AML patients receiving ORY-1001.
March 12, 2018: Cancer Cell
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