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Lysine specific demethylase

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https://www.readbyqxmd.com/read/28534506/lsd1-demethylates-hif1%C3%AE-to-inhibit-hydroxylation-and-ubiquitin-mediated-degradation-in-tumor-angiogenesis
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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 1, 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
#7
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...
April 13, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28450737/writing-erasing-and-reading-histone-lysine-methylations
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28430662/histone-demethylase-jmjd3-regulates-cd11a-expression-through-changes-in-histone-h3k27-tri-methylation-levels-in-cd4-t-cells-of-patients-with-systemic-lupus-erythematosus
#11
Heng Yin, Haijing Wu, Ming Zhao, Qing Zhang, Hai Long, Siqi Fu, Qianjin Lu
Aberrant CD11a overexpression in CD4+ T cells induces T cell auto-reactivity, which is an important factor for systemic lupus erythematosus (SLE) pathogenesis. Although many studies have focused on CD11a epigenetic regulation, little is known about histone methylation. JMJD3, as a histone demethylase, is capable of specifically removing the trimethyl group from the H3K27 lysine residue, triggering target gene activation. Here, we examined the expression and function of JMJD3 in CD4+ T cells from SLE patients...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#12
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28422711/melatonin-exerts-anti-oral-cancer-effect-via-suppressing-lsd1-in-patient-derived-tumor-xenograft-models
#13
Cheng-Yu Yang, Chih-Kung Lin, Chang-Huei Tsao, Cheng-Chih Hsieh, Gu-Jiun Lin, Kuo-Hsing Ma, Yi-Shing Shieh, Huey-Kang Sytwu, Yuan-Wu Chen
Aberrant activation of histone lysine-specific demethylase (LSD1) increases tumorigenicity; hence, LSD1 is considered a therapeutic target for various human cancers. Although melatonin, an endogenously produced molecule, may defend against various cancers, the precise mechanism involved in its anti-oral cancer effect remains unclear. Patient-derived tumor xenograft (PDTX) models are preclinical models that can more accurately reflect human tumor biology compared with cell line xenograft models. Here, we evaluated the anticancer activity of melatonin by using LSD1-overexpressing oral cancer PDTX models...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416760/the-histone-demethylase-kdm3a-regulates-the-transcriptional-program-of-the-androgen-receptor-in-prostate-cancer-cells
#14
Stephen Wilson, Lingling Fan, Natasha Sahgal, Jianfei Qi, Fabian V Filipp
The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity, and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416745/stable-h3-peptide-was-delivered-by-gold-nanorods-to-inhibit-lsd1-activation-and-induce-human-mesenchymal-stem-cells-differentiation
#15
Xin Meng, Jianping Li, Minjuan Zheng, Lei Zuo, Chao Sun, Yongsheng Zhu, Ling Fang, Liwen Liu, Xiaodong Zhou
Recently, lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, regulates post-translational modifications and has great promise as new targets for cancer and other diseases. Moreover, the ability of LSD1 to induce the differentiation of stem cells has attracted great attention in biological fields. In this study, we designed LSD1 peptide inhibitor based on its substrate H3 peptide. Through introducing a disulfide bond to stabilize the native peptide into alpha helical structure, we get a peptide with higher cell permeability and stability compared to its parent form...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414096/lysine-specific-demethylase-1-lsd1-depletion-disrupts-monogenic-and-monoallelic-odorant-receptor-or-expression-in-an-olfactory-neuronal-cell-line
#16
Rutesh N Vyas, Diane Meredith, Robert P Lane
Function of the mammalian olfactory system depends on specialized olfactory sensory neurons (OSNs) that each express only one allele ("monoallelic") of one odorant receptor (OR) gene ("monogenic"). The lysine-specific demethylase-1 (LSD1) protein removes activating H3K4 or silencing H3K9 methylation marks in a variety of developmental contexts, and is thought to be important for proper OR regulation. Most of the focus in the field has been on a potential "activating" function for LSD1; e.g., in the demethylation of H3K9 associated with the expressed OR allele...
April 13, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28408473/o-glcnacylation-and-chromatin-remodeling-in-mammals-an-up-to-date-overview
#17
REVIEW
Maïté Leturcq, Tony Lefebvre, Anne-Sophie Vercoutter-Edouart
Post-translational modifications of histones and the dynamic DNA methylation cycle are finely regulated by a myriad of chromatin-binding factors and chromatin-modifying enzymes. Epigenetic modifications ensure local changes in the architecture of chromatin, thus controlling in fine the accessibility of the machinery of transcription, replication or DNA repair to the chromatin. Over the past decade, the nutrient-sensor enzyme O-GlcNAc transferase (OGT) has emerged as a modulator of chromatin remodeling. In mammals, OGT acts either directly through dynamic and reversible O-GlcNAcylation of histones and chromatin effectors, or in an indirect manner through its recruitment into chromatin-bound multiprotein complexes...
April 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28404874/identification-of-jl1037-as-a-novel-specific-reversible-lysine-specific-demethylase-1-inhibitor-that-induce-apoptosis-and-autophagy-of-aml-cells
#18
Shuang Liu, Wenting Lu, Shouyun Li, Saisai Li, Jia Liu, Yuanyuan Xing, Shuzu Zhang, Joe Zhongxiang Zhou, Haiyan Xing, Yingxi Xu, Qing Rao, Chengjun Deng, Min Wang, Jianxiang Wang
Lysine-specific demethylase 1 (LSD1) has been recognized as a potential therapeutic target for acute myeloid leukemia (AML). Herein, we identified a novel LSD1 inhibitor, JL1037, via Computer Aided Drug Design technology. JL1037 is a potent, selective and reversible LSD1 inhibitor with IC50s of 0.1 μM and >1.5 μM for LSD1 and monoamine oxidases A/B (MAO-A/B), respectively. Treatment of THP-1 and Kasumi-1 cell lines with JL1037 resulted in dose dependent accumulation of H3K4me1 and H3K4me2, the major substrates of LSD1, as well as inhibition of cell proliferation, blockade of cell cycle and induction of apoptosis...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28390942/fluorinated-tranylcypromine-analogues-as-inhibitors-of-lysine-specific-demethylase-1-lsd1-kdm1a
#19
Maria Teresa Borrello, Benjamin Schinor, Katharina Bartels, Hanae Benelkebir, Sara Pereira, Wafa T Al-Jamal, Leon Douglas, Patrick J Duriez, Graham Packham, Günter Haufe, A Ganesan
We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.
March 29, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28381185/the-histone-demethylase-lysine-specific-demethylase-1-mediated-epigenetic-silence-of-klf2-contributes-to-gastric-cancer-cell-proliferation-migration-and-invasion
#20
Ruizhong Fang, Jian Xu, Hai Lin, Xiaoguang Xu, Feng Tian
Gastric cancer is one of the most common malignancies and leading causes of cancer-related death worldwide. An increasing number of evidence has revealed that gastric tumorigenesis is a multistage pathological state, and epigenetic alterations are considered to play critical roles in the etiology of gastric cancer. Lysine-specific demethylase-1, a histone demethylase, has been linked to malignancy in several human cancers and considered to epigenetically regulate many tumor suppressor genes during tumorigenesis and cancer progression...
April 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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