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lysine demethylase

Coralie Poulard, Estelle Baulu, Brian H Lee, Miles A Pufall, Michael R Stallcup
Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1γ (HP1γ) as another required coactivator...
October 10, 2018: Cell Death & Disease
Haiqi Mu, Luxia Xiang, Shaoxun Li, Dapang Rao, Shuaibin Wang, Kaiyuan Yu
Deregulation of microRNAs contributes to the abnormal cell growth which is frequently observed in cancer. In the current study, we detected the expression and regulatory relationship between miR-10a and Lysine-specific demethylase 4A (KDM4A) to reveal their function in prostate cancer (PCa) progression. We found that miR-10a levels were significantly decreased in PCa cell lines in comparison with the normal epithelial cell line RWPE-1. Downregulation of miR-10a levels was also observed in tumor tissues from PCa patients compared with the adjacent normal tissues...
October 9, 2018: Journal of Cellular Biochemistry
Yosuke Ota, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is one of the flavin-dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1...
September 11, 2018: Chemical Record: An Official Publication of the Chemical Society of Japan ... [et Al.]
Shumei Liang, Qingmin Yao, Deying Wei, Ming Liu, Feng Geng, Qin Wang, Yun-Shan Wang
KDM6B, also known as JMJD3, is a member of the family of histone lysine demethylase (KDMs), which is closely related to many types of cancers. However, its role and the underlying mechanisms in ovarian cancer remain unknown. Here we show that KDM6B is elevated in epithelial ovarian cancer and its expression level is closely related with metastasis and invasion. In addition, survival analysis showed that high expression of KDM6B was associated with low overall survival in ovarian cancer patients. Overexpression of KDM6B in epithelial ovarian cancer cells promoted proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in vitro, and enhanced metastatic capacities in vivo...
September 11, 2018: Journal of Cellular Biochemistry
Sungjin Ko, Jacquelyn O Russell, Jianmin Tian, Ce Gao, Makoto Kobayashi, Rilu Feng, Xiaodong Yuan, Chen Shao, Huiguo Ding, Minakshi Poddar, Sucha Singh, Joseph Locker, Hong-Lei Weng, Satdarshan P Monga, Donghun Shin
BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration...
September 26, 2018: Gastroenterology
Ashima Saxena, Tatyana Belinskaya, Lawrence M Schopfer, Oksana Lockridge
Milk of the domestic pig has 10 times more butyrylcholinesterase (BChE) per mL than porcine serum. We purified BChE from porcine milk by affinity chromatography on Hupresin-Sepharose. The pure porcine BChE (PoBChE) was a tetramer with a molecular weight of 340,000, similar to that of human BChE tetramers. The C-terminal 40 residues of PoBChE constitute the tetramerization domain. The glue that holds the 4 BChE subunits together is a polyproline-rich peptide. Mass spectrometry analysis of trypsin-digested PoBChE identified a variety of polyproline-rich peptides originating from 12 different proteins...
October 2018: Data in Brief
Zhaoming Lu, Yandan Ren, Mengying Zhang, Tianli Fan, Yang Wang, Qi Zhao, Hong-Min Liu, Wen Zhao, Guiqin Hou
Aberrant activation of the Notch signaling plays an important role in progression of esophageal squamous cell carcinoma (ESCC) and may represent a potential therapeutic target for ESCC. FLI-06 is a novel Notch inhibitor, preventing the early secretion of Notch signaling. However, little information about the antitumor activity of FLI-06 has been reported so far. To evaluate the anti-tumor activity and possible molecular mechanism of FLI-06 to ESCC cells, the effects of FLI-06 on cell viability, apoptosis and cell cycle were evaluated by CCK-8 and flow cytometry assays, respectively, in ESCC cell lines ECa109 and EC9706, and the expressions of proteins in Notch signaling pathway and LSD1 were investigated after cells were treated with FLI-06 by Western blotting...
November 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Haishan Lin, Guowei Yang, Jing Yu, Jing Wang, Qin Li, Shuilong Guo, Bangwei Cao
OBJECTIVE: The study aimed to study the effect of histone methyltransferase KDM5c (Lysine(K)-specific demethylase 5C) on drug resistance in colon cancer cells. METHODS: KDM5c expression interference was performed using empty plasmids, SMCV-dGFP-KDM5c plasmids and siControl, siKDM5c transfected human colon cancer HCT-8, RKO cell lines, and then grouped into NC, KDM5c-OE, siControl, siKDM5c groups.0.625 μg /ml, 1.25 μg/ml, 2.5 μg/ml, 5 μg/ml, 10 μg/ml, and 20 μg/ml oxaliplatin (L-OHP), and 0...
November 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Alba Maiques-Diaz, James T Lynch, Gary J Spencer, Tim C P Somervaille
Pharmacologic inhibition of KDM1A (Lysine Demethylase 1A) induces differentiation in certain subtypes of acute myeloid leukemia. Our recent studies reveal this is dependent upon drug-induced disruption of the GFI1 (Growth Factor Independent 1) transcription repressor complex, leading to activation of enhancers distributed close to genes controlling monocytic lineage differentiation.
2018: Molecular & Cellular Oncology
J Plch, J Hrabeta, T Eckschlager
Histone methylation is important in the regulation of genes expression, and thus its dysregulation has been observed in various cancers. KDM5 enzymes are capable of removing tri- and di- methyl marks from lysine 4 on histone H3 (H3K4) which makes them potential players in the downregulation of tumour suppressors, but could also suggest that their activity repress oncogenes. Depending on the methylation site, their effect on transcription can be either activating or repressing. There is emerging evidence for deregulation of KDM5A/B/C/D and important phenotypic consequences in various types of cancer...
September 24, 2018: International Journal of Cancer. Journal International du Cancer
Federica Sarno, Chiara Papulino, Gianluigi Franci, Jeanette H Andersen, Bastien Cautain, Colombina Melardo, Lucia Altucci, Angela Nebbioso
Despite the discovery and development of novel therapies, cancer is still a leading cause of death worldwide. In order to grow, tumor cells require large quantities of nutrients involved in metabolic processes, and an increase in iron levels is known to contribute to cancer proliferation. Iron plays an important role in the active site of a number of proteins involved in energy metabolism, DNA synthesis and repair, such as ribonucleotide reductase, which induce G0/S phase arrest and exert a marked antineoplastic effect, particularly in leukemia and neuroblastoma...
2018: Frontiers in Pharmacology
Yani Zheng, Yongbo Xue, Xingjie Ren, Mengmeng Liu, Xiao Li, Yu Jia, Ye Niu, Jian-Quan Ni, Yong Zhang, Jun-Yuan Ji
Post-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive depending on specific pathological contexts...
2018: Frontiers in Genetics
Robert R Haines, Benjamin G Barwick, Christopher D Scharer, Parimal Majumder, Troy D Randall, Jeremy M Boss
B cells undergo epigenetic remodeling as they differentiate into Ab-secreting cells (ASC). LSD1 is a histone demethylase known to decommission active enhancers and cooperate with the ASC master regulatory transcription factor Blimp-1. The contribution of LSD1 to ASC formation is poorly understood. In this study, we show that LSD1 is necessary for proliferation and differentiation of mouse naive B cells (nB) into plasmablasts (PB). Following LPS inoculation, LSD1-deficient hosts exhibited a 2-fold reduction of splenic PB and serum IgM...
September 19, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Thiru Prasanna, Fan Wu, Kum Kum Khanna, Desmond Yip, Laeeq Malik, Jane Dahlstrom, Sudha Rao
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination (HR) DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival...
September 19, 2018: Cancer Science
Keri Callegari, Shinji Maegawa, Javiera Bravo-Alegria, Vidya Gopalakrishnan
BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors. METHODS: Expression of LSD1 was examined across a publicly-available database and correlated with patient outcomes...
September 18, 2018: Cell Communication and Signaling: CCS
Iris F Macheleidt, Priya S Dalvi, So-Young Lim, Sonja Meemboor, Lydia Meder, Olivia Käsgen, Marion Müller, Karolin Kleemann, Lingyu Wang, Peter Nürnberg, Vanessa Rüsseler, Stephan C Schäfer, Esther Mahabir, Reinhard Büttner, Margarete Odenthal
Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5-year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine-specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD...
September 16, 2018: Molecular Oncology
Nicolas Lebrun, Claire Mehler-Jacob, Karine Poirier, Cecile Zordan, Didier Lacombe, Nathalie Carion, Pierre Billuart, Thierry Bienvenu
Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals...
September 12, 2018: Gene
Ji-Hyun Kim, Dae Young Jung, Arulkumar Nagappan, Myeong Ho Jung
Understanding the epigenetic mechanisms underlying the progression of hepatic steatosis is important for identifying new therapeutic targets against nonalcoholic fatty liver disease (NAFLD). We investigated the functional role of histone demethylase JMJD2B in the pathologic regulation of hepatic steatosis. JMJD2B expression was markedly increased in HepG2 cells treated with palmitate and oleate or liver X receptor agonist T09013178 and in the liver of high-fat diet (HFD)-induced obese mice. Overexpression of JMJD2B using adenovirus in HepG2 cells stimulated the expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) and its steatosis target genes associated with fatty acid uptake and lipid droplet formation, resulting in increased intracellular triglyceride (TG) accumulation...
September 13, 2018: Scientific Reports
Meina Yan, Xinxin Yang, Hui Wang, Qixiang Shao
The discovery of histone demethylases has revealed the dynamic nature of the regulation of histone methylation. KDM2B is an important histone lysine demethylase that removes methyl from H3K36me2 and H3K4me3. It participates in many aspects of normal cellular processes such as cell senescence, cell differentiation and stem cell self-renewal. Recent studies also showed that KDM2B was overexpressed in various types of cancers. This review focuses primarily on the current knowledge of KDM2B and its function in cancer development...
2018: American Journal of Translational Research
Susanna Ambrosio, Andrea Ballabio, Barbara Majello
Macroautophagy/autophagy is a physiological mechanism that is essential for the maintenance of cellular homeostasis and stress adaptation. Defective autophagy is associated with many human diseases, including cancer and neurodegenerative disorders. The emerging implication of epigenetic events in the control of the autophagic process opens new avenues of investigation and offers the opportunity to develop novel therapeutic strategies in diseases associated with dysfunctional autophagy-lysosomal pathways. Accumulating evidence reveals that several methyltransferases and demethylases are essential regulators of autophagy, and recent studies have led to the identification of the lysine demethylase KDM1A/LSD1 as a promising drug target...
September 13, 2018: Autophagy
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