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lysine demethylase

Xiao Xu, Wenhui Peng, Cuiyun Liu, Sixuan Li, Jiali Lei, Zhen Wang, Lingyi Kong, Chao Han
Lysine-specific demethylase 1 (LSD1) has recently emerged as a therapeutic target for cancer. However, almost all LSD1 inhibitors developed to date are chemo-synthesised molecules. In this study, the LSD1 inhibitory activity of 12 natural flavones, including four aglycones and their corresponding monoglycosides and diglucosides, was evaluated. Based on the structure-activity relationships, LSD1 inhibition activity was greater for flavonoid monoglycosides than their aglycones lacking the sugar moiety. The effects of isoquercitrin, which exhibited optimal LSD1 inhibitory activity, on cancer cell properties were evaluated...
December 7, 2018: Bioorganic & Medicinal Chemistry
Sarder Arifuzzaman, Md Saidur Rahman, Myung-Geol Pang
With the continued increase in global human population, diverse contraception approaches have become increasingly essential, including non-hormonal male contraception. Non-hormonal approaches to contraception are very convenient; however, such options are limited because data regarding the identification and characterization of tissue/cell-specific targets and appropriate small molecule candidate contraceptives are lacking. Based on in-silico studies of genomics, transcriptomics, and proteomics, performed by mining datasets in PubMed, we first reviewed testis-, epididymis-, and germline cell-specific genes/proteins, with the aim of presenting evidence that many of these could become 'druggable' targets for the development of non-hormonal male contraceptives in the future...
December 11, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Qing-Jun Zhang, Tram Anh T Tran, Ming Wang, Mark J Ranek, Kristen M Kokkonen-Simon, Jason Gao, Xiang Luo, Wei Tan, Viktoriia Kyrychenko, Lan Liao, Jianming Xu, Joseph A Hill, Eric N Olson, David A Kass, Elisabeth D Martinez, Zhi-Ping Liu
Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload...
December 7, 2018: Nature Communications
Fangyuan Dong, Shuheng Jiang, Jun Li, Yahui Wang, Lili Zhu, Yiqin Huang, Xin Jiang, Xiaona Hu, Qi Zhou, Zhigang Zhang, Zhijun Bao
BACKGROUND: Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. METHODS: Primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. Loss-of-function experiments were applied to determine the cellular functions of KDM4D in HSCs...
December 5, 2018: EBioMedicine
Youni Kim, Youngeun Jeong, Kujin Kwon, Tayaba Ismail, Hyun-Kyung Lee, Chowon Kim, Jeen-Woo Park, Oh-Shin Kwon, Beom-Sik Kang, Dong-Seok Lee, Tae Joo Park, Taejoon Kwon, Hyun-Shik Lee
BACKGROUND: Lysine-specific histone demethylase 5C (KDM5C) belongs to the jumonji family of demethylases and is specific for the di- and tri-demethylation of lysine 4 residues on histone 3 (H3K4 me2/3). KDM5C is expressed in the brain and skeletal muscles of humans and is associated with various biologically significant processes. KDM5C is known to be associated with X-linked mental retardation and is also involved in the development of cancer. However, the developmental significance of KDM5C has not been explored yet...
December 6, 2018: Epigenetics & Chromatin
Kimberly N Smitheman, Tesa M Severson, Satyajit R Rajapurkar, Michael T McCabe, Natalie Karpinich, James Foley, Melissa B Pappalardi, Ashley Hughes, Wendy Halsey, Elizabeth Thomas, Christopher Traini, Kelly E Federowicz, Jenny Laraio, Fredrick Mobegi, Geraldine Ferron-Brady, Rabinder K Prinjha, Christopher L Carpenter, Ryan G Kruger, Lodewyk Wessels, Helai P Mohammad
Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described.1 Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all-trans retinoic acid was explored...
December 4, 2018: Haematologica
Zhimei Guo, Fang Liu, Hai Jun Li
BACKGROUND: Kabuki syndrome (KS) is a rare congenital anomaly syndrome affecting multiple organs. Two genes have been shown to be mutated in patients with KS: lysine (K)-specific demethylase 6A (KDM6A) and lysine (K)-specific methyltransferase 2D (KMT2D, formerly MLL2). Although the congenital clinical characteristic is helpful in diagnosis of the KS, there are no reports of specific findings in fetuses that might suggest the syndrome prenatally. CASE PRESENTATION: In this study, we described a male patient with a novel KDM6A splicing in exon(exon4) and flanking intron(intron3)-exon boundaries characterized by congenital hydrocephalus which had never been reported before...
December 3, 2018: BMC Medical Genetics
Haoqing Yang, Jiao Fan, Yangyang Cao, Runtao Gao, Zhipeng Fan
Understanding the mechanism of osteo-/dentinogenic differentiation is beneficial for jaw bone and dental tissue regeneration. DLX5 is highly expressed in dental tissue-derived mesenchymal stem cells (MSCs) and is upregulated by lysine-specific demethylase 4B (KDM4B), enabling it to regulate osteo-/dentinogenic differentiation, while the function of DLX5 in osteo-/dentinogenesis has not been thoroughly elucidated to date. Therefore, we investigated DLX5 function using stem cells from apical papilla (SCAPs). SCAPs were obtained from the human wisdom tooth...
November 29, 2018: Experimental Cell Research
Zhong-Rui Li, Feng-Zhi Suo, Bo Hu, Yan-Jia Guo, Dong-Jun Fu, Bin Yu, Yi-Chao Zheng, Hong-Min Liu
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting...
November 16, 2018: Bioorganic Chemistry
Li-Juan Zhao, Ting Zhang, Xue-Jian Feng, Jiao Chang, Feng-Zhi Suo, Jin-Lian Ma, Ying-Jun Liu, Ying Liu, Yi-Chao Zheng, Hong-Min Liu
USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0...
November 28, 2018: Journal of Cellular Biochemistry
Dan-Hua Lu, Jiang Yang, Li-Kun Gao, Jie Min, Jian-Ming Tang, Ming Hu, Yang Li, Su-Ting Li, Jing Chen, Li Hong
Metastasis is the most common cause of death in ovarian cancer patients but remains largely untreated. Epithelial‑mesenchymal transition (EMT) is critical for the conversion of early‑stage ovarian tumors into metastatic malignancies. Thus, investigating the signaling pathways promoting EMT may identify potential targets for the treatment of metastatic ovarian cancer. Lysine demethylase 2A (KDM2A), also known as FBXL11 and JHDM1A, is a histone H3 lysine 36 (H3K36) demethylase that regulates EMT and the metastasis of ovarian cancer...
November 27, 2018: Oncology Reports
Taotao Shou, Huyin Yang, Jia Lv, Dai Liu, Xiaoyang Sun
MicroRNAs (miRNAs) are acknowledged as essential regulators in human cancer types, including glioblastoma (GBM). However, the functions of microRNA‑3666 (miR‑3666) in GBM remain unclear. In the present study, it was identified that the expression of miR‑3666 was significantly downregulated in GBM tissues compared with adjacent normal tissues by reverse transcription‑quantitative polymerase chain reaction. Additionally, miR‑3666 was downregulated in GBM cell lines. Furthermore, it was observed that the miR‑3666 expression level in patients with GBM was associated with prognosis...
November 27, 2018: Molecular Medicine Reports
Qi-Sheng Ma, Yongfang Yao, Yi-Chao Zheng, Siqi Feng, Junbiao Chang, Bin Yu, Hong-Min Liu
Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50  = 6...
November 17, 2018: European Journal of Medicinal Chemistry
Kesong Peng, Lele Kou, Li Yu, Chaonan Bai, Ming Li, Pingli Mo, Wengang Li, Chundong Yu
BACKGROUND & AIMS: Wnt signaling contributes to development of colorectal cancer (CRC). We studied interactions between lysine demethylase 4D (KDM4D or JMJD2D) and beta-catenin, a mediator of Wnt signaling, in CRC cell lines and the effects on tumor formation in mice. METHODS: We obtained colorectal tumor specimens and surrounding non-tumor colon tissues (controls) from patients undergoing surgery in China; levels of JMJD2D were measured by immunohistochemical or immunoblot analysis...
November 22, 2018: Gastroenterology
Kunihiko Hinohara, Hua-Jun Wu, Sébastien Vigneau, Thomas O McDonald, Kyomi J Igarashi, Kimiyo N Yamamoto, Thomas Madsen, Anne Fassl, Shawn B Egri, Malvina Papanastasiou, Lina Ding, Guillermo Peluffo, Ofir Cohen, Stephen C Kales, Madhu Lal-Nag, Ganesha Rai, David J Maloney, Ajit Jadhav, Anton Simeonov, Nikhil Wagle, Myles Brown, Alexander Meissner, Piotr Sicinski, Jacob D Jaffe, Rinath Jeselsohn, Alexander A Gimelbrant, Franziska Michor, Kornelia Polyak
Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors...
November 14, 2018: Cancer Cell
Xudong Sun, Lina Ding, Hong-Min Liu
Lysine specific demethylase 1 (LSD1) has emerged as a potential drug target in cancer therapy and a variety of inhibitors have been reported. We have recently reported the discovery of a series of triazole-dithiocarbamate based compounds, which were basically confirmed as cofactor flavin adenine dinucleotide (FAD)-competing inhibitors by experiments. However, the binding modes of the inhibitors to the binding site were undetermined. Here, we employed computational methods including molecular docking, classical molecular dynamics (MD) and steered molecular dynamics (SMD) simulations to investigate the potential binding modes of these inhibitors to LSD1...
November 23, 2018: Physical Chemistry Chemical Physics: PCCP
Elyn M Rowe, Viktoria Xing, Kyle K Biggar
Lysine methylation is well-documented and relatively well-understood with respect to histone modification and the epigenetic regulation of gene expression. Enzymes called lysine methyltransferases (KMTs) are capable of methylating lysine residues on histone tails, while the opposing lysine demethylases (KDMs) are capable of removing the methyl groups. This balance of dynamic methylation of histone proteins effectively alters gene expression, and has been widely studied with many applications in neurological disease...
November 19, 2018: Brain Research
Lei Yu, Natee Jearawiriyapaisarn, Mary P Lee, Tomonori Hosoya, Qingqing Wu, Greggory Myers, Kim-Chew Lim, Ryo Kurita, Yukio Nakamura, Anne B Vojtek, Jean-François Rual, James Douglas Engel
Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e...
November 21, 2018: Genes & Development
Alexandre Fellous, Ryan L Earley, Frederic Silvestre
Histone modifications such as methylation of key lysine residues play an important role in embryonic development in a variety of organisms such as of Pacific oysters, zebrafish and mice. The action of demethylase ("erasers") and methyltransferase ("writers") enzymes regulates precisely the methylation status of each lysine residue. However, despite fishes being very useful model organisms in medicine, evolution and ecotoxicology, most studies have focused on mammalian and plant model organisms, and mechanisms underlying regulation of histones are unknown in fish development outside of zebrafish...
November 17, 2018: Gene
Keisuke Tamari, Masamitsu Konno, Ayumu Asai, Jun Koseki, Kazuhiko Hayashi, Koichi Kawamoto, Noriyuki Murai, Senya Matsufuji, Fumiaki Isohashi, Taroh Satoh, Noriko Goto, Shinji Tanaka, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa, Hideshi Ishii
Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs...
2018: Cell Death Discovery
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