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https://www.readbyqxmd.com/read/28817399/chemotherapy-for-oligometastatic-prostate-cancer
#1
Tanya B Dorff, Christopher J Sweeney
PURPOSE OF REVIEW: To analyze recent trials of upfront chemotherapy to determine how this paradigm can be applied to oligometastatic prostate cancer patients. RECENT FINDINGS: Upfront chemotherapy prolongs survival in metastatic prostate cancer, according to the ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer and STAMPEDE docetaxel trials. However, the benefit is driven by the high volume subset and may not apply to low-volume/oligometastatic patients...
August 16, 2017: Current Opinion in Urology
https://www.readbyqxmd.com/read/28816576/a-demethylation-deficient-isoform-of-the-lysine-demethylase-kdm2a-interacts-with-pericentromeric-heterochromatin-in-an-hp1a-dependent-manner
#2
Dijana Lađinović, Jitka Novotná, Soňa Jakšová, Ivan Raška, Tomáš Vacík
Histone modifications have a profound impact on the chromatin structure and gene expression and their correct establishment and recognition is essential for correct cell functioning. Malfunction of histone modifying proteins is associated with developmental defects and diseases and detailed characterization of these proteins is therefore very important. The lysine specific demethylase KDM2A is a CpG island binding protein that has been studied predominantly for its ability to regulate CpG island-associated gene promoters by demethylating their H3K36me2...
August 17, 2017: Nucleus
https://www.readbyqxmd.com/read/28811844/lsd1-dual-function-in-mediating-epigenetic-corruption-of-the-vitamin-d-signaling-in-prostate-cancer
#3
Sebastiano Battaglia, Ellen Karasik, Bryan Gillard, Jennifer Williams, Trisha Winchester, Michael T Moser, Dominic J Smiraglia, Barbara A Foster
BACKGROUND: Lysine-specific demethylase 1A (LSD1) is a key regulator of the androgen (AR) and estrogen receptors (ER), and LSD1 levels correlate with tumor aggressiveness. Here, we demonstrate that LSD1 regulates vitamin D receptor (VDR) activity and is a mediator of 1,25(OH)2-D3 (vitamin D) action in prostate cancer (PCa). METHODS: Athymic nude mice were xenografted with CWR22 cells and monitored weekly after testosterone pellet removal. Expression of LSD1 and VDR (IHC) were correlated with tumor growth using log-rank test...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28811501/characterisation-of-sterol-biosynthesis-and-validation-of-14%C3%AE-demethylase-as-a-drug-target-in-acanthamoeba
#4
Scott Thomson, Christopher A Rice, Tong Zhang, RuAngelie Edrada-Ebel, Fiona L Henriquez, Craig W Roberts
The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14α-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811299/twenty-years-of-menin-emerging-opportunities-for-restoration-of-transcription-in-men1
#5
Koen M A Dreijerink, Marc Timmers, Myles Brown
Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin modifying enzymes, in particular the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin...
August 15, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28810288/overexpression-of-demeter-a-dna-demethylase-promotes-early-apical-bud-maturation-in-poplar
#6
Daniel Conde, Alicia Moreno-Cortés, Christopher Dervinis, José M Ramos-Sánchez, Matias Kirst, Mariano Perales, Pablo González-Melendi, Isabel Allona
The transition from active growth to dormancy is critical for the survival of perennial plants. We identified a DEMETER-like (CsDML) cDNA from a winter-enriched cDNA subtractive library in chestnut (Castanea sativa Mill.), an economically and ecologically important species. Next, we characterized this DNA demethylase and its putative orthologue in the more experimentally tractable hybrid poplar (Populus tremula x alba), under the signals that trigger bud dormancy in trees. We performed phylogenetic and protein sequence analysis, gene expression profiling and 5mC immunodetection studies to evaluate the role of CsDML and its homologue in poplar, PtaDML6...
August 15, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28809490/electrophilic-zinc-homoenolates-synthesis-of-cyclopropylamines-from-cyclopropanols-and-amines
#7
L Reginald Mills, Luis Miguel Barrera Arbelaez, Sophie A L Rousseaux
Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of β-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy...
August 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28808009/a-protein-complex-regulates-rna-processing-of-intronic-heterochromatin-containing-genes-in-arabidopsis
#8
Cheng-Guo Duan, Xingang Wang, Lingrui Zhang, Xiansong Xiong, Zhengjing Zhang, Kai Tang, Li Pan, Chuan-Chih Hsu, Huawei Xu, W Andy Tao, Heng Zhang, Jian-Kang Zhu
In several eukaryotic organisms, heterochromatin (HC) in the introns of genes can regulate RNA processing, including polyadenylation, but the mechanism underlying this regulation is poorly understood. By promoting distal polyadenylation, the bromo-adjacent homology (BAH) domain-containing and RNA recognition motif-containing protein ASI1 and the H3K9me2-binding protein EDM2 are required for the expression of functional full-length transcripts of intronic HC-containing genes in Arabidopsis Here we report that ASI1 and EDM2 form a protein complex in vivo via a bridge protein, ASI1-Immunoprecipitated Protein 1 (AIPP1), which is another RNA recognition motif-containing protein...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28806732/loss-of-the-chromatin-modifier-kdm2aa-causes-brafv600e-independent-spontaneous-melanoma-in-zebrafish
#9
Catherine M Scahill, Zsofia Digby, Ian M Sealy, Sonia Wojciechowska, Richard J White, John E Collins, Derek L Stemple, Till Bartke, Marie E Mathers, E Elizabeth Patton, Elisabeth M Busch-Nentwich
KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28802152/comparison-and-analysis-of-the-structures-and-binding-modes-of-antifungal-se-and-cyp51-inhibitors
#10
Bin Sun, Wanxu Huang, Min Liu, Kang Lei
With the abuse of clinical broad-spectrum antimicrobial agents, immunosuppressive agents, chemotherapy drugs, the emergence of pathogenic fungi resistance is more and more frequent. However, there is still no effective treatment for the fungal resistance. Squalenee epoxidase (SE) and 14 α-demethylase (CYP51) are important antifungal drug targets. In order to achieve a deeper insight into the structural characteristics and the action modes of SE and CYP51inhibitors, the homology model of SE (Candida albicans) was constructed using monooxygenase of Pseudomonas aeruginosa as template, and the reliability of model was confirmed by Ramachandran plots and Verify 3D...
August 1, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28800922/inhibition-of-h3k4-demethylation-induces-autophagy-in-cancer-cell-lines
#11
Zhen Wang, Qiao-Yun Long, Lin Chen, Jia-Dong Fan, Zhao-Ning Wang, Lian-Yun Li, Min Wu
Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA...
August 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28798687/tet2-protects-against-oxldl-induced-huvec-dysfunction-by-upregulating-the-cse-h2s-system
#12
Juan Peng, Zhi-Han Tang, Zhong Ren, Bei He, Yun Zeng, Lu-Shan Liu, Zuo Wang, Dang-Heng Wei, Xi-Long Zheng, Zhi-Sheng Jiang
Ten-eleven translocation-2 (TET2) protein is a DNA demethylase that regulates gene expression through DNA demethylation and also plays important roles in various diseases including atherosclerosis. Endothelial dysfunction represents an early key event in atherosclerotic disease. The cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) is a key endogenous system with protective effects on endothelial functions. In this study, we examined how TET2 regulates oxidized low-density lipoprotein (oxLDL)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and determined the role of the CSE/H2S system...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28793246/endoglin-is-essential-for-the-maintenance-of-self-renewal-and-chemoresistance-in-renal-cancer-stem-cells
#13
Junhui Hu, Wei Guan, Peijun Liu, Jin Dai, Kun Tang, Haibing Xiao, Yuan Qian, Allison C Sharrow, Zhangqun Ye, Lily Wu, Hua Xu
Renal cell carcinoma (RCC) is a deadly malignancy due to its tendency to metastasize and resistance to chemotherapy. Stem-like tumor cells often confer these aggressive behaviors. We discovered an endoglin (CD105)-expressing subpopulation in human RCC xenografts and patient samples with a greater capability to form spheres in vitro and tumors in mice at low dilutions than parental cells. Knockdown of CD105 by short hairpin RNA and CRISPR/cas9 reduced stemness markers and sphere-formation ability while accelerating senescence in vitro...
August 8, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28790329/kdm4b-mediated-reduction-of-h3k9me3-and-h3k36me3-levels-improves-somatic-cell-reprogramming-into-pluripotency
#14
Jingwei Wei, Jisha Antony, Fanli Meng, Paul MacLean, Rebekah Rhind, Götz Laible, Björn Oback
Correct reprogramming of epigenetic marks is essential for somatic cells to regain pluripotency. Repressive histone (H) lysine (K) methylation marks are known to be stable and difficult to reprogram. In this study, we generated transgenic mice and mouse embryonic fibroblasts (MEFs) for the inducible expression of KDM4B, a demethylase that removes H3 K9 and H3K36 trimethylation (me3) marks (H3K9/36me3). Upon inducing Kdm4b, H3K9/36me3 levels significantly decreased compared to non-induced controls. Concurrently, H3K9me1 levels significantly increased, while H3K9me2 and H3K27me3 remained unchanged...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790175/antibody-mediated-blockade-of-jmjd6-interaction-with-collagen-i-exerts-antifibrotic-and-antimetastatic-activities
#15
Silvia Miotti, Alessandro Gulino, Renata Ferri, Mariella Parenza, Agnieszka Chronowska, Daniele Lecis, Sabina Sangaletti, Elda Tagliabue, Claudio Tripodo, Mario P Colombo
JMJD6 is known to localize in the nucleus exerting histone arginine demethylase and lysyl hydroxylase activities. A novel localization of JMJD6 in the extracellular matrix, resulting from its secretion as a soluble protein, was unveiled by a new anti-JMJD6 mAb called P4E11 which was developed to identify new targets in the stroma. Recombinant JMJD6 binds with collagen type I (Coll-I), and distinct JMJD6 peptides interfere with collagen fibrillogenesis, collagen-fibronectin interaction, and adhesion of human tumor cells to the collagen substrate...
August 8, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28783174/lysine-specific-demethylase-lsd1-regulates-autophagy-in-neuroblastoma-through-sesn2-dependent-pathway
#16
S Ambrosio, C D Saccà, S Amente, S Paladino, L Lania, B Majello
Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells...
August 7, 2017: Oncogene
https://www.readbyqxmd.com/read/28778066/inhibition-of-lsd1-epigenetically-attenuates-oral-cancer-growth-and-metastasis
#17
Saqer F Alsaqer, Mustafa M Tashkandi, Vinay K Kartha, Ya-Ting Yang, Yazeed Alkheriji, Andrew Salama, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti, Manish V Bais
Lysine-specific demethylase 1 (LSD1) is a nuclear histone demethylase and a member of the amine oxidase (AO) family. LSD1 is a flavin-containing AO that specifically catalyzes the demethylation of mono- and di-methylated histone H3 lysine 4 through an FAD-dependent oxidative reaction. LSD1 is inappropriately upregulated in lung, liver, brain and esophageal cancers, where it promotes cancer initiation, progression, and metastasis. However, unlike other lysine-specific demethylases, the role and specific targets of LSD1 in oral squamous cell carcinoma (OSCC) pathogenesis remain unknown...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28777546/site-selective-sensing-of-histone-methylation-enzyme-activity-via-an-arrayed-supramolecular-tandem-assay
#18
Yang Liu, Lizeth Perez, Adam D Gill, Magi Mettry, Lin Li, Yinsheng Wang, Richard J Hooley, Wenwan Zhong
Arrayed deep cavitands can be coupled to a fluorescence-based supramolecular tandem assay that allows site-selective in situ monitoring of post-translational modifications catalyzed by the lysine methyltransferase PRDM9 or the lysine demethylase JMJD2E. An arrayed sensor system containing only three cavitand components can detect the specific substrates of enzyme modification, in the presence of other histone peptides in the enzyme assay, enabling investigation of cross-reactivity over multiple methylation sites and interference from nonsubstrate peptides...
August 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28776568/clinical-analysis-of-nsclc-patients-reveals-lack-of-association-between-egfr-mutation-and-tet1-downregulation
#19
J-I Lai, Y-C Lai, Y-C Chen, N-K Wang, J-N Pan, W-S Wang, S-C Chang
Lung cancer is one of the leading causes of death from cancer worldwide, with a poor prognosis in advanced cases. In the past decade, epidermal growth factor receptor (EGFR) inhibitors have shown significant efficacy towards treatment for EGFR mutant lung cancer. Expanding our knowledge of oncogenic EGFR signaling pathways is therefore of highly importance for the cancer field. Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer...
August 4, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28765946/histone-demethylase-phf8-accelerates-the-progression-of-colorectal-cancer-and-can-be-regulated-by-mir-488-in%C3%A2-vitro
#20
Yao Lv, Yan Shi, Quanli Han, Guanghai Dai
Plant homeo domain finger protein 8 (PHF8), as an oncogene, has been highlighted in cancer development and progression. However, its clinical significance and underlying molecular mechanisms in colorectal cancer (CRC) remain to be fully elucidated. In the present study, the role of PHF8 in the progression of CRC was investigated. The mRNA and protein levels of PHF8 in tissues from patients with CRC and cell lines were detected using the reverse transcription-quantitative polymerase chain reaction and western blotting, respectively...
August 1, 2017: Molecular Medicine Reports
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