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https://www.readbyqxmd.com/read/29331452/design-synthesis-and-evaluation-of-%C3%AE-turn-mimetics-as-lsd1-selective-inhibitors
#1
Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity...
January 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29331085/verification-of-dna-motifs-in-arabidopsis-using-crispr-cas9-mediated-mutagenesis
#2
Chenlong Li, Chen Chen, Huhui Chen, Suikang Wang, Xuemei Chen, Yuhai Cui
Transcription factors (TFs) and chromatin-modifying factors (CMFs) access chromatin by recognizing specific DNA motifs in their target genes. Chromatin Immunoprecipitation followed by next generation sequencing (ChIP-seq) has been widely used to discover the potential DNA binding motifs for both TFs and CMFs. Yet, an in vivo method for verifying DNA motifs captured by ChIP-seq is lacking in plants. Here, we describe the use of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) to verify DNA motifs in their native genomic context in Arabidopsis...
January 13, 2018: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29330049/the-histone-demethylase-phf8-promotes-adult-acute-lymphoblastic-leukemia-through-interaction-with-the-mek-erk-signaling-pathway
#3
Yue Fu, Yaling Yang, Xiaoming Wang, Xiaolin Yin, Minran Zhou, Siqi Wang, Lin Yang, Tao Huang, Man Xu, Chunyan Chen
Adult acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that is associated with a high risk of relapse and poor prognosis. Thus, novel pathogenic mechanisms and therapeutic targets need to be explored. Histone methylation is one of the most significant chromatin post-translational modifications. Here, we show that the histone demethylase PHF8 is highly expressed in a large number of ALL clinical specimens and that PHF8 expression is associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes the apoptosis of ALL cells in vitro as well as attenuates tumor growth in vivo...
January 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29324315/histone-demethylase-kdm5a-inhibits-glioma-cells-migration-and-invasion-by-down-regulating-zeb1
#4
Bin Dai, Hui Huang, Feng Guan, Guangtong Zhu, Zhiyong Xiao, Beibei Mao, Haiyang Su, Zhiqiang Hu
Malignant gliomas are highly lethal cancers worldwide as tumor cells infiltrate to healthy brain tissue invariably. Histone demethylase KDM5A as an oncogene or tumor suppressor in cancer still has been controversial. KDM5A may have a different function in different type cancer cells. However, the specific roles of KDM5A in the progression of glioma remain undiscovered. In this study, we found that compared with primary glioma, metastasis glioma had low KDM5A levels. Besides, lower KDM5A levels were linked to poor survival in glioma cancer patients, indicating that KDM5A is a new prognostic marker for glioma cancer...
January 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29323165/biotransformation-and-tissue-distribution-of-protopine-and-allocryptopine-and-effects-of-plume-poppy-total-alkaloid-on-liver-drug-metabolizing-enzymes
#5
Ya-Jun Huang, Pi Cheng, Zhuo-Yi Zhang, Shi-Jie Tian, Zhi-Liang Sun, Jian-Guo Zeng, Zhao-Ying Liu
In this study, the biotransformation in the plasma, urine and feces of rats following oral administration of protopine (PRO) and allocryptopine (ALL)were explored using HPLC-QqTOF MS. An HPLC-MS/MS method for the determination of tissues was developed and applied to the tissue distribution study in rats following intragastric administration of Plume Poppy Total Alkaloid for 3 weeks. A total of ten PRO metabolites and ten ALL metabolites were characterized in rats in vivo. Among these metabolites, six PRO metabolites and five ALL metabolites were reported for the first time...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321178/transcription-factor-dependent-anti-repressive-mammalian-enhancers-exclude-h3k27me3-from-extended-genomic-domains
#6
Madhurima Saxena, Adrianna K San Roman, Nicholas K O'Neill, Rita Sulahian, Unmesh Jadhav, Ramesh A Shivdasani
Compacted chromatin and nucleosomes are known barriers to gene expression; the nature and relative importance of other transcriptional constraints remain unclear, especially at distant enhancers. Polycomb repressor complex 2 (PRC2) places the histone mark H3K27me3 predominantly at promoters, where its silencing activity is well documented. In adult tissues, enhancers lack H3K27me3, and it is unknown whether intergenic H3K27me3 deposits affect nearby genes. In primary intestinal villus cells, we identified hundreds of tissue-restricted enhancers that require the transcription factor (TF) CDX2 to prevent the incursion of H3K27me3 from adjoining areas of elevated basal marking into large well-demarcated genome domains...
January 10, 2018: Genes & Development
https://www.readbyqxmd.com/read/29319811/identification-of-a-consensus-motif-in-erg28p-required-for-c-4-demethylation-in-yeast-ergosterol-biosynthesis-based-on-mutation-analysis
#7
Xia Ke, Xiao-Yuan Xia, Ren-Chao Zheng, Yu-Guo Zheng
The Erg28p protein is localized to the endoplasmic reticulum (ER), where it acts as a scaffold to tether the C-4 demethylase complex involved in the sterol biosynthesis pathway of Saccharomyces cerevisiae. However, due to the challenges involved in characterizing the interactions of membrane proteins, the precise region of Erg28p that is responsible for the assembly of this enzyme complex remains unknown. To address this question, mutants with serial truncations in the C-terminus of Erg28p were constructed based on a topology prediction of its transmembrane domain...
January 8, 2018: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/29317619/phf8-histone-demethylase-deficiency-causes-cognitive-impairments-through-the-mtor-pathway
#8
Xuemei Chen, Shuai Wang, Ying Zhou, Yanfei Han, Shengtian Li, Qing Xu, Longyong Xu, Ziqi Zhu, Youming Deng, Lu Yu, Lulu Song, Adele Pin Chen, Juan Song, Eiki Takahashi, Guang He, Lin He, Weidong Li, Charlie Degui Chen
Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 (Phf8) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29317521/ca2-dependent-demethylation-of-phosphatase-pp2ac-promotes-glucose-deprivation-induced-cell-death-independently-of-inhibiting-glycolysis
#9
Ha Yin Lee, Yoko Itahana, Stefan Schuechner, Masahiro Fukuda, H Shawn Je, Egon Ogris, David M Virshup, Koji Itahana
Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation initiates a cell death pathway in cancer cells that is dependent on the kinase RIPK1. Glucose withdrawal triggered rapid plasma membrane depolarization and an influx of extracellular calcium into the cell through the L-type calcium channel Cav1.3 (CACNA1D), followed by activation of the kinase CAMK1...
January 9, 2018: Science Signaling
https://www.readbyqxmd.com/read/29315835/fto-regulates-the-chemo-radiotherapy-resistance-of-cervical-squamous-cell-carcinoma-cscc-by-targeting-%C3%AE-catenin-through-mrna-demethylation
#10
Shun Zhou, Zhou-Lan Bai, Di Xia, Zhi-Jun Zhao, Ren Zhao, Yan-Yang Wang, Hong Zhe
The role of N6 -methyladenosine (m6 A) demethylase Fat Mass and Obesity-associated protein (FTO) in the regulation of chemo-radiotherapy resistance remains largely unknown. Here, we show that the mRNA level of FTO is elevated in cervical squamous cell carcinoma (CSCC) tissues when compared with respective adjacent normal tissues. FTO enhances the chemo-radiotherapy resistance both in vitro and in vivo through regulating expression of β-catenin by reducing m6 A levels in its mRNA transcripts and in turn increases excision repair cross-complementation group 1 (ERCC1) activity...
January 9, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29311580/lsd1-activation-promotes-inducible-emt-programs-and-modulates-the-tumour-microenvironment-in-breast-cancer
#11
T Boulding, R D McCuaig, A Tan, K Hardy, F Wu, J Dunn, M Kalimutho, C R Sutton, J K Forwood, A G Bert, G J Goodall, L Malik, D Yip, J E Dahlstrom, A Zafar, K K Khanna, S Rao
Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29303998/linking-dna-damage-and-age-related-promoter-dna-hyper-methylation-in-the-intestine
#12
Torsten Thalheim, Maria Herberg, Joerg Galle
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Here, we explore whether and how DNA damage repair might impact on these time-dependent changes, in particular in proliferative intestinal stem cells. We introduce a 3D multiscale computer model of intestinal crypts enabling simulation of aberrant DNA and histone methylation of gene promoters during aging. We assume histone state-dependent activity of de novo DNA methyltransferases (DNMTs) and methylation-dependent binding of maintenance DNMTs to CpGs...
January 5, 2018: Genes
https://www.readbyqxmd.com/read/29302625/quantitation-of-ergosterol-content-and-gene-expression-profile-of-erg11-gene-in-fluconazole-resistant-candida-albicans
#13
F Alizadeh, A Khodavandi, S Zalakian
Background and Purpose: The frequency of opportunistic fungal infections in immunocompromised patients, especially by Candida species, has sharply increased in the last few decades. The objective of this study was to analyse the ergosterol content and gene expression profiling of clinical isolates of fluconazole-resistant Candida albicans. Materials and Methods: Sixty clinical samples were identified and collected from immunocompromised patients, namely recurrent oral, vaginal, and cutaneous candidiasis, during 2015-16...
March 2017: Advances in Medical Mycology (Iran)
https://www.readbyqxmd.com/read/29302039/targeting-the-corest-complex-with-dual-histone-deacetylase-and-demethylase-inhibitors
#14
Jay H Kalin, Muzhou Wu, Andrea V Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J Roberts, Justin M Roberts, Polina Prusevich, Jeliazko R Jeliazkov, Shourya S Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M Proby, Albena T Dinkova-Kostova, Wayne W Hancock, Jeffrey J Gray, James E Bradner, Sergio Valente, Antonello Mai, Nicole M Anders, Michelle A Rudek, Yong Hu, Byungwoo Ryu, John W R Schwabe, Andrea Mattevi, Rhoda M Alani, Philip A Cole
Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes...
January 4, 2018: Nature Communications
https://www.readbyqxmd.com/read/29301935/-inhibition-of-histone-h3k27-demethylase-selectively-modulates-inflammatory-phenotypes-of-natural-killer-cells
#15
Adam Cribbs, Edward S Hookway, Graham Wells, Morten Lindow, Susanna Obad, Henrik Oerum, Rab K Prinjha, Nick Athanasou, Aneka Sowman, Martin Philpott, Henry Penn, Kalle Soderstrom, Marc Feldmann, Udo Oppermann
Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically, but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29298815/genome-wide-characterisation-of-dna-methylation-in-an-invasive-lepidopteran-pest-the-cotton-bollworm-helicoverpa-armigera
#16
Christopher M Jones, Ka S Lim, Jason W Chapman, Chris Bass
The genes and genomes of insect pests are shaped by the wide array of selective forces encountered in their environments. While the molecular adaptations that evolve are beginning to be understood at the genomic and transcriptomic level they have been less well characterised at an epigenetic level. Here, we present a genome-wide map of DNA methylation, at single-nucleotide resolution for the cotton bollworm moth, Helicoverpa armigera; a globally invasive pest of agriculture. We show that methylation is almost identical in the larvae and adults of H...
January 3, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29290786/kdm5b-overexpression-predicts-a-poor-prognosis-in-patients-with-squamous-cell-carcinoma-of-the-head-and-neck
#17
Donghai Huang, Yuanzheng Qiu, Guo Li, Chao Liu, Li She, Diekuo Zhang, Xiyu Chen, Gangcai Zhu, Xin Zhang, Yongquan Tian, Yong Liu
Purpose: Lysine demethylase (KDM) 5B, as a member of the histone lysine demethylase family, is overexpressed and functions abnormally in various human cancers. However, its expression in the squamous cell carcinoma of the head and neck (SCCHN) remains unclear. Methods: KDM5B expression was analyzed by immunohistochemistry and correlated with clinicopathological parameters in 103 archival SCCHN tissue samples and 24 adjacent noncancerous epithelial tissues. Results: We found that KDM5B expression was higher in SCCHN than that in adjacent noncancerous tissues...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29289682/l-ascorbic-acid-a-true-substrate-for-hif-proly-hydroxylase
#18
A I Osipyants, A A Poloznikov, N A Smirnova, D M Hushpulian, A Yu Khristichenko, T A Chubar, A A Zakhariants, M Ahuja, I N Gaisina, B Thomas, A M Brown, I G Gazaryan, V I Tishkov
L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif...
December 28, 2017: Biochimie
https://www.readbyqxmd.com/read/29286083/kdm3a-inhibition-attenuates-high-concentration-insulin%C3%A2-induced-vascular-smooth-muscle-cell-injury-by-suppressing-mapk-nf%C3%A2-%C3%AE%C2%BAb-pathways
#19
Bo-Fang Zhang, Hong Jiang, Jing Chen, Xin Guo, Qi Hu, Shuo Yang
Previous studies have indicated that lysine (K)‑specific demethylase 3A (KDM3A) is associated with diverse diabetes‑associated cardiovascular complications in response to high glucose levels. However, the effects of KDM3A on the pathological progression of cardiovascular injuries in response to high insulin levels remain unknown. The present study aimed to explore whether KDM3A knockdown may attenuate high insulin‑induced vascular smooth muscle cell (VSMC) dysfunction, and to further investigate the underlying mechanisms...
December 29, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29284029/cyp51-is-an-essential-drug-target-for-the-treatment-of-primary-amoebic-meningoencephalitis-pam
#20
Anjan Debnath, Claudia M Calvet, Gareth Jennings, Wenxu Zhou, Alexander Aksenov, Madeline R Luth, Ruben Abagyan, W David Nes, James H McKerrow, Larissa M Podust
Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug 'repurposing'-a cost effective strategy to apply known drugs for treatment of rare or neglected diseases...
December 2017: PLoS Neglected Tropical Diseases
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