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Epigenetic resistance

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https://www.readbyqxmd.com/read/27913493/novel-agents-in-follicular-lymphoma-choosing-the-best-target
#1
Laurie H Sehn
Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27912843/the-reduced-concentration-of-citrate-in-cancer-cells-an-indicator-of-cancer-aggressiveness-and-a-possible-therapeutic-target
#2
Icard Philippe, Lincet Hubert
Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy...
November 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/27907135/the-histone-deacetylase-gene-rpd3-is-required-for-starvation-stress-resistance
#3
Ei Nakajima, Kouhei Shimaji, Takanari Umegawachi, Saki Tomida, Hideki Yoshida, Nana Yoshimoto, Shingo Izawa, Hiroshi Kimura, Masamitsu Yamaguchi
Epigenetic regulation in starvation is important but not fully understood yet. Here we identified the Rpd3 gene, a Drosophila homolog of histone deacetylase 1, as a critical epigenetic regulator for acquiring starvation stress resistance. Immunostaining analyses of Drosophila fat body revealed that the subcellular localization and levels of Rpd3 dynamically changed responding to starvation stress. In response to starvation stress, the level of Rpd3 rapidly increased, and it accumulated in the nucleolus in what appeared to be foci...
2016: PloS One
https://www.readbyqxmd.com/read/27907095/phenotypic-plasticity-epigenetic-or-genetic-modifications-in-relation-to-the-duration-of-cd-exposure-within-a-microevolution-time-range-in-the-beet-armyworm
#4
Maria Augustyniak, Anna Płachetka-Bożek, Alina Kafel, Agnieszka Babczyńska, Monika Tarnawska, Agnieszka Janiak, Anna Loba, Marta Dziewięcka, Julia Karpeta-Kaczmarek, Agnieszka Zawisza-Raszka
In the case of the pests inhabiting metal polluted or fields where the use of pesticides is common, a natural selection of resistant individuals can occur. This may pose serious problems for humans, agriculture, as well as the economies of many countries. In this study, the hypothesis that multigenerational (120 generations) exposure to cadmium of a beet armyworm population could be a selecting factor toward a more efficient DNA protection was verified. The hemocytes of individuals from two culture strains (control and Cd-exposed) were treated with H2O2 (a DNA-damaging agent) or PBS (reference)...
2016: PloS One
https://www.readbyqxmd.com/read/27905578/2-r-fluorinated-mc-hmc-fc-and-cac-triphosphates-are-substrates-for-dna-polymerases-and-tet-enzymes
#5
A S Schröder, E Parsa, K Iwan, F R Traube, M Wallner, S Serdjukow, T Carell
A deeper investigation of the chemistry that occurs on the newly discovered epigenetic DNA bases 5-hydroxymethyl-(hmdC), 5-formyl-(fdC), and 5-carboxy-deoxycytidine (cadC) requires chemical tool compounds, which are able to dissect the different potential reaction pathways in cells. Here we report that the 2'-(R)-fluorinated derivatives F-hmdC, F-fdC, and F-cadC, which are resistant to removal by base excision repair, are good substrates for DNA polymerases and TET enzymes. This result shows that the fluorinated compounds are ideal tool substances to investigate potential C-C-bond cleaving reactions in the context of active demethylation...
December 1, 2016: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/27905327/potential-therapeutic-effect-of-epigenetic-therapy-on-treatment-induced-neuroendocrine-prostate-cancer
#6
Xiang Xu, Yu-Hua Huang, Yan-Jing Li, Alexa Cohen, Zhen Li, Jill Squires, Wei Zhang, Xu-Feng Chen, Min Zhang, Jiao-Ti Huang
Although adenocarcinomas of the prostate are relatively indolent, some patients with advanced adenocarcinomas show recurrence of treatment-induced neuroendocrine prostate cancer, which is highly aggressive and lethal. Detailed biological features of treatment-induced neuroendocrine prostate cancer have not been characterized owing to limited biopsies/resections and the lack of a cellular model. In this study, we used a unique cellular model (LNCaP/NE1.8) to investigate the potential role of cancer stem cells in treatment-induced neuroendocrine prostate cancer with acquired resistance to hormonal therapy and chemotherapy...
November 29, 2016: Asian Journal of Andrology
https://www.readbyqxmd.com/read/27904654/augmentation-of-histone-deacetylase-3-hdac3-epigenetic-signature-at-the-interface-of-proinflammation-and-insulin-resistance-in-patients-with-type-2-diabetes
#7
Chandrakumar Sathishkumar, Paramasivam Prabu, Mahalingam Balakumar, Raji Lenin, Durai Prabhu, Ranjith Mohan Anjana, Viswanathan Mohan, Muthuswamy Balasubramanyam
BACKGROUND: A role of proinflammation has been implicated in the pathogenesis of diabetes, but the up-stream regulatory signals and molecular signatures are poorly understood. While histone modifications such as changes in histone deacetylase (HDAC) are emerging as novel epigenetic biomarkers, there is lack of studies to demonstrate their clinical relevance in diabetes. Therefore, we investigated the extent of HDAC machinery and inflammatory signals in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes mellitus (T2DM) compared to control subjects...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27903230/glucocorticoid-receptor-interacting-co-regulators-putative-candidates-for-future-drug-targeting-therapy
#8
Alessia Di Silvestre, Marianna Lucafò, Sara De Iudicibus, Alessandro Ventura, Stefano Martelossi, Gabriele Stocco, Giuliana Decorti
Glucocorticoids (GCs) are largely used in different inflammatory, autoimmune and proliferative diseases. To date their mechanism of action is not completely clear and more studies are necessary, in particular to explain the great interindividual variability in clinical response. In this panorama the glucocorticoid receptor (GR) has an important role: in fact it regulates the pharmacological response thanks to the capability to interact with different molecules (DNA, RNA, ncRNA and proteins) that are known to influence its activity...
November 29, 2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/27895808/mendelian-inheritance-of-trimodal-cpg-methylation-sites-suggests-distal-cis-acting-genetic-effects
#9
Shaza B Zaghlool, Mashael Al-Shafai, Wadha A Al Muftah, Pankaj Kumar, Christian Gieger, Melanie Waldenberger, Mario Falchi, Karsten Suhre
BACKGROUND: Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such "heritable" CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian. METHODS: Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27893715/tgf%C3%AE-promotes-mesenchymal-phenotype-of-pancreatic-cancer-cells-in-part-through-epigenetic-activation-of-vav1
#10
P-H Huang, P-J Lu, L-Y Ding, P-C Chu, W-Y Hsu, C-S Chen, C-C Tsao, B-H Chen, C-T Lee, Y-S Shan, C-S Chen
The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27893709/identification-of-myst3-as-a-novel-epigenetic-activator-of-er%C3%AE-frequently-amplified-in-breast-cancer
#11
L Yu, Y Liang, X Cao, X Wang, H Gao, S-Y Lin, R Schiff, X-S Wang, K Li
Estrogen receptor α (ERα) is a master driver of a vast majority of breast cancers. Breast cancer cells often develop resistance to endocrine therapy via restoration of the ERα activity through survival pathways. Thus identifying the epigenetic activator of ERα that can be targeted to block ERα gene expression is a critical topic of endocrine therapy. Here, integrative genomic analysis identified MYST3 as a potential oncogene target that is frequently amplified in breast cancer. MYST3 is involved in histone acetylation via its histone acetyltransferase domain (HAT) and, as a result, activates gene expression by altering chromatin structure...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27889327/epigenetics-in-non-alcoholic-fatty-liver-disease
#12
REVIEW
Jooho Lee, Yuri Kim, Simonetta Friso, Sang-Woon Choi
Non-alcoholic fatty liver disease (NAFLD), a common hepatic disorder ranging from simple steatosis through steatohepatitis to fibrosis and cirrhosis, is an emerging health concern. NAFLD is a pathologic condition characterized by the buildup of extra fat in liver cells that is not caused by alcohol consumption. Excess hepatic fat accumulation results from increased delivery of triglycerides (TG) to the liver or conversion of surplus carbohydrates to TG. Importantly, a subgroup of NAFLD results in hepatocellular injury and inflammation, which is referred to as non-alcoholic steatohepatitis (NASH), and may progress to irreversible cirrhosis and hepatocellular carcinoma (HCC)...
November 23, 2016: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/27888136/different-epigenetic-mechanisms-of-er%C3%AE-implicated-in-the-fate-of-fulvestrant-resistant-breast-cancer
#13
Kouki Tsuboi, Yosuke Kaneko, Takamasa Nagatomo, Rika Fujii, Toru Hanamura, Tatsuyuki Gohno, Yuri Yamaguchi, Toshifumi Niwa, Shin-Ichi Hayashi
Approximately 70% of breast cancers express estrogen receptor α (ERα), which plays critical roles in breast cancer development. Fulvestrant has been effectively used to treat ERα-positive breast cancer, although resistance remains a critical problem. To elucidate the mechanism of resistance to fulvestrant, we established fulvestrant-resistant cell-lines named MFR (MCF-7 derived fulvestrant resistance) and TFR (T-47D derived fulvestrant resistance) from the ERα-positive luminal breast cancer cell lines MCF-7 and T-47D, respectively...
November 22, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27887656/looking-beyond-the-cancer-cell-for-effective-drug-combinations
#14
Jonathan R Dry, Mi Yang, Julio Saez-Rodriguez
Combinations of therapies are being actively pursued to expand therapeutic options and deal with cancer's pervasive resistance to treatment. Research efforts to discover effective combination treatments have focused on drugs targeting intracellular processes of the cancer cells and in particular on small molecules that target aberrant kinases. Accordingly, most of the computational methods used to study, predict, and develop drug combinations concentrate on these modes of action and signaling processes within the cancer cell...
November 25, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27882346/epigenetic-regulation-of-macrophage-polarization-and-inflammation-by-dna-methylation-in-obesity
#15
Xianfeng Wang, Qiang Cao, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi
Obesity is associated with increased classically activated M1 adipose tissue macrophages (ATMs) and decreased alternatively activated M2 ATMs, both of which contribute to obesity-induced inflammation and insulin resistance. However, the underlying mechanism remains unclear. We find that inhibiting DNA methylation pharmacologically using 5-aza-2'-deoxycytidine or genetically by DNA methyltransferase 1 (DNMT1) deletion promotes alternative activation and suppresses inflammation in macrophages. Consistently, mice with myeloid DNMT1 deficiency exhibit enhanced macrophage alternative activation, suppressed macrophage inflammation, and are protected from obesity-induced inflammation and insulin resistance...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27880937/prognostic-relevance-of-mirna-155-methylation-in-anaplastic-glioma
#16
Maximilian Georg Schliesser, Rainer Claus, Thomas Hielscher, Christiane Grimm, Dieter Weichenhan, Jonas Blaes, Benedikt Wiestler, Peter Hau, Johannes Schramm, Felix Sahm, Elisa K Weiß, Markus Weiler, Constance Baer, Friederike Schmidt-Graf, Gabriele Schackert, Manfred Westphal, Anne Hertenstein, Patrick Roth, Norbert Galldiks, Christian Hartmann, Torsten Pietsch, Joerg Felsberg, Guido Reifenberger, Michael Christoph Sabel, Frank Winkler, Andreas von Deimling, Christoph Meisner, Peter Vajkoczy, Michael Platten, Michael Weller, Christoph Plass, Wolfgang Wick
The outcome of patients with anaplastic gliomas varies considerably depending on single molecular markers, such as mutations of the isocitrate dehydrogenase (IDH) genes, as well as molecular classifications based on epigenetic or genetic profiles. Remarkably, 98% of the RNA within a cell is not translated into proteins. Of those, especially microRNAs (miRNAs) have been shown not only to have a major influence on physiologic processes but also to be deregulated and prognostic in malignancies.To find novel survival markers and treatment options we performed unbiased DNA methylation screens that revealed 12 putative miRNA promoter regions with differential DNA methylation in anaplastic gliomas...
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27876670/a-model-of-dynamic-stability-of-h3k9me3-heterochromatin-to-explain-the-resistance-to-reprogramming-of-differentiated-cells
#17
Charly Jehanno, Gilles Flouriot, Pascale Le Goff, Denis Michel
Despite their dynamic nature, certain chromatin marks must be maintained over the long term. This is particulary true for histone 3 lysine 9 (H3K9) trimethylation, that is involved in the maintenance of healthy differentiated cellular states by preventing inappropriate gene expression, and has been recently identified as the most efficient barrier to cellular reprogramming in nuclear transfer experiments. We propose that the capacity of the enzymes SUV39H1/2 to rebind to a minor fraction of their products, either directly or via HP1α/β, contributes to the solidity of this mark through (i) a positive feedback involved in its establishment by the mutual enforcement of H3K9me3 and SUV39H1/2 and then (ii) a negative feedback sufficient to strongly stabilize H3K9me3 heterochromatin in post-mitotic cells by generating local enzyme concentrations capable of counteracting transient bursts of demethylation...
November 20, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27872099/conflicting-signals-for-cancer-treatment
#18
Pierre Sujobert, Alain Trautmann
Next-generation sequencing technologies have provided us with a precise description of the mutational burden of cancers, making it possible to identify targetable oncogene addictions. However, the emergence of resistant clones is an inevitable limitation of therapies targeting these addictions. Alternative approaches to cancer treatment are therefore required. We propose here a novel approach, based on the notion of conflicting signals and on a phenotypic description of cancer cells. "Phenotype" is an inherently complex notion that we describe in the conceptual framework of the epigenetic landscape, with a view to bridging the gap between theory and practice at the patient's bedside...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27872090/mutational-landscape-of-pediatric-acute-lymphoblastic-leukemia
#19
LingWen Ding, Qiao-Yang Sun, Kar-Tong Tan, Wenwen Chien, Anand Mayakonda Thippeswamy, Allen Yeoh Eng Juh, Norihiko Kawamata, Yasunobu Nagata, Jin-Fen Xiao, Xin-Yi Loh, De-Chen Lin, Manoj Garg, Su-Lin Lim, Li-Zhen Liu, Vikas Madan, Yan-Yi Jiang, Liang Xu, Masashi Sanada, Lucia Torres Fernández, Hema Preethi, Michael Lill, Hagop Kantarjian, S M Kornblau, Satoru Miyano, Seishi Ogawa, Der-Cherng Liang, Lee-Yung Shih, Henry Yang, H Phillip Koeffler
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here we report the use of next generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment and the p53/cell cycle pathway...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27871873/itraq-based-proteomic-analysis-of-defence-responses-triggered-by-the-necrotrophic-pathogen-rhizoctonia-solani-in-cotton
#20
Min Zhang, Shou-Ting Cheng, Hai-Yun Wang, Jia-He Wu, Yuan-Ming Luo, Qian Wang, Fu-Xin Wang, Gui-Xian Xia
: The soil-borne necrotrophic pathogen fungus Rhizoctonia solani is destructive, causing disease in various important crops. To date, little is known about the host defence mechanism in response to invasion of R. solani. Here, an iTRAQ-based proteomic analysis was employed to investigate pathogen-responsive proteins in the disease tolerant/resistant cotton cultivar CRI35. A total of 174 differentially accumulated proteins (DAPs) were identified after inoculation of cotton plants with R...
November 15, 2016: Journal of Proteomics
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