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Epigenetic resistance

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https://www.readbyqxmd.com/read/28338971/progressive-silencing-of-the-zinc-transporter-zip8-slc39a8-in-chronic-cadmium-exposed-lung-epithelial-cells
#1
Yangmin Gao, Yanming Xu, Dandan Wu, Feiyuan Yu, Lei Yang, Yue Yao, Zhanling Liang, Andy T Y Lau
Cadmium (Cd), a non-essential metal, stealthily enters the cells by utilizing the essential metal importing pathways. The zinc transporters Zip8, Zip14, and divalent metal transporter 1 (Dmt1) are now emerging as several important metal transporters involved in cellular Cd incorporation and their expressions have been shown to be down-regulated in several Cd-resistant (CdR) cell lines, however, the involvement of these transporters during the development of Cd-resistance in lung cells is unclear. In this study, we therefore check the expression of these metal transporters in our previously established rat lung epithelial cells (LECs) and show that the level of Zip8 is progressively silenced when LECs are adapted to increasing concentrations of CdCl2 (from 1 to 20 μM)...
March 18, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28332584/akt-targeting-as-a-strategy-to-boost-chemotherapy-efficacy-in-non-small-cell-lung-cancer-through-metabolism-suppression
#2
Marion Le Grand, Raphael Berges, Eddy Pasquier, Marie-Pierre Montero, Laurence Borge, Alice Carrier, Sophie Vasseur, Veronique Bourgarel, Duje Buric, Nicolas André, Diane Braguer, Manon Carré
Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28324831/primary-and-acquired-resistance-to-pd-1-pd-l1-blockade-in-cancer-treatment
#3
REVIEW
Qiaohong Wang, Xia Wu
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous...
March 18, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28323978/assisted-reproductive-technologies-predispose-to-insulin-resistance-and-obesity-in-male-mice-challenged-with-a-high-fat-diet
#4
David Cerny, Claudio Sartori, Stefano F Rimoldi, Théo Meister, Rodrigo Soria, Elisa Bouillet, Urs Scherrer, Emrush Rexhaj
ART alters glucose homeostasis in mice and humans, but the underlying mechanisms are incompletely understood. ART induces endothelial dysfunction and arterial hypertension by epigenetic alteration of the eNOS gene. In eNOS deficient mice, insulin resistance is related to impaired insulin stimulation of muscle blood flow and substrate delivery and defective intrinsic skeletal muscle glucose uptake. We, therefore, assessed glucose tolerance, insulin sensitivity (euglycemic clamp), insulin stimulation of muscle blood flow in vivo and muscle glucose uptake in vitro in male ART and control mice fed a normal chow (NC) or challenged with a high fat diet (HFD) during 8 weeks...
February 8, 2017: Endocrinology
https://www.readbyqxmd.com/read/28320962/genetic-disruption-of-oncogenic-kras-sensitizes-lung-cancer-cells-to-fas-receptor-mediated-apoptosis
#5
Haiwei Mou, Jill Moore, Sunil K Malonia, Yingxiang Li, Deniz M Ozata, Soren Hough, Chun-Qing Song, Jordan L Smith, Andrew Fischer, Zhiping Weng, Michael R Green, Wen Xue
Genetic lesions that activate KRAS account for ∼30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small-molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras Here, we show that tumor cells can survive knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus, even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment...
March 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28320484/nutritional-intervention-preconception-and-during-pregnancy-to-maintain-healthy-glucose-metabolism-and-offspring-health-nipper-study-protocol-for-a-randomised-controlled-trial
#6
Keith M Godfrey, Wayne Cutfield, Shiao-Yng Chan, Philip N Baker, Yap-Seng Chong
BACKGROUND: Improved maternal nutrition and glycaemic control before and during pregnancy are thought to benefit the health of the mother, with consequent benefits for infant body composition and later obesity risk. Maternal insulin resistance and glycaemia around conception and in early pregnancy may be key determinants of maternal physiology and placental function, affecting fetal nutrient supply and maternal-feto-placental communications throughout gestation, with implications for later postnatal health...
March 20, 2017: Trials
https://www.readbyqxmd.com/read/28320277/mechanisms-of-brain-glucocorticoid-resistance-in-stress-induced-psychopathologies
#7
REVIEW
V M Merkulov, T I Merkulova, N P Bondar
Exposure to stress activates the hypothalamic-pituitary-adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications...
March 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28318385/arsenic-induced-sumoylation-of-mus81-is-involved-in-regulating-genomic-stability
#8
Liyan Hu, Feikun Yang, Lou Lu, Wei Dai
Chronic environmental exposure to metal toxicants such as chromium and arsenic is closely related to the development of several types of common cancers. Genetic and epigenetic studies in the past decade reveal that post-translational modifications of histones play a role in metal carcinogenesis. However, exact molecular mechanisms of metal carcinogenesis remain to be elucidated. In this study we found that As2O3, an environmental metal toxicant, up-regulated overall modifications of many cellular proteins by SUMO2/3...
March 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28303890/baf60b-mediated-atm-p53-activation-blocks-cell-identity-conversion-by-sensing-chromatin-opening
#9
Shuyi Ji, Linying Zhu, Yimeng Gao, Xiaoran Zhang, Yupeng Yan, Jin Cen, Rongxia Li, Rong Zeng, Lujian Liao, Chunhui Hou, Yawei Gao, Shaorong Gao, Gang Wei, Lijian Hui
Lineage conversion by expression of lineage-specific transcription factors is a process of epigenetic remodeling that has low efficiency. The mechanism by which a cell resists lineage conversion is largely unknown. Using hepatic-specific transcription factors Foxa3, Hnf1α and Gata4 (3TF) to induce hepatic conversion in mouse fibroblasts, we showed that 3TF induced strong activation of the ATM-p53 pathway, which led to proliferation arrest and cell death, and it further prevented hepatic conversion. Notably, ATM activation, independent of DNA damage, responded to chromatin opening during hepatic conversion...
March 17, 2017: Cell Research
https://www.readbyqxmd.com/read/28302915/sex-differences-in-ischaemic-stroke-potential-cellular-mechanisms
#10
REVIEW
Anjali Chauhan, Hope Moser, Louise D McCullough
Stroke remains a leading cause of mortality and disability worldwide. More women than men have strokes each year, in part because women live longer. Women have poorer functional outcomes, are more likely to need nursing home care and have higher rates of recurrent stroke compared with men. Despite continued advancements in primary prevention, innovative acute therapies and ongoing developments in neurorehabilitation, stroke incidence and mortality continue to increase due to the aging of the U.S. POPULATION: Sex chromosomes (XX compared with XY), sex hormones (oestrogen and androgen), epigenetic regulation and environmental factors all contribute to sex differences...
April 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28302822/the-cancer-epigenome-concepts-challenges-and-therapeutic-opportunities
#11
REVIEW
Mark A Dawson
Cancer biology is profoundly influenced by changes in the epigenome. Because the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. In this review, I provide a broad context for recent developments that offer a greater understanding of how epigenetic regulators facilitate the initiation, maintenance, and evolution of cancer. I discuss newly developed epigenetic therapies and the cellular and molecular mechanisms that may govern sensitivity and resistance to these agents...
March 17, 2017: Science
https://www.readbyqxmd.com/read/28300634/combination-of-chemotherapy-and-cancer-stem-cell-targeting-agents-preclinical-and-clinical-studies
#12
Yanyan Li, Katharine Atkinson, Tao Zhang
The cancer stem cell model claims that the initiation, maintenance, and growth of a tumor are driven by a small population of cancer cells termed cancer stem cells. Cancer stem cells possess a variety of phenotypes associated with therapeutic resistance and often cause recurrence of the diseases. Several strategies have been investigated to target cancer stem cells in a variety of cancers, such as blocking one or more self-renewal signaling pathways, reducing the expression of drug efflux and ATP-binding cassette efflux transporters, modulating epigenetic aberrations, and promoting cancer stem cell differentiation...
March 11, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28292214/adamtsl5-and-cdh11-putative-epigenetic-markers-for-therapeutic-resistance-in-acute-lymphoblastic-leukemia
#13
Maha Abdullah, Chee Wei Choo, Hamidah Alias, Eni Juraidah Abdul Rahman, Hishamshah Mohd Ibrahim, Rahman Jamal, Noor Hamidah Hussin
BACKGROUND AND OBJECTIVES: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers. METHODS: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips...
March 15, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28291773/comprehensive-molecular-exploration-identified-promoter-dna-methylation-of-the-crbp1-gene-as-a-determinant-of-radiation-sensitivity-in-rectal-cancer
#14
K Yokoi, K Yamashita, S Ishii, T Tanaka, N Nishizawa, A Tsutsui, H Miura, H Katoh, T Yamanashi, M Naito, T Sato, T Nakamura, M Watanabe
BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) for advanced rectal cancer (RC) is a well-evidenced therapy; however, some RC patients have no therapeutic response. Patient selection for NCRT so that non-responsive patients are excluded has been subjective. To date, no molecular markers indicating radiation sensitivity have been reported. METHODS: We irradiated six colorectal cancer (CRC) cell lines and identified HCT116 cells as radiation-sensitive and HCT15 and DLD-1 cells as radiation resistant...
March 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28291256/exercise-rescues-obese-mothers-insulin-sensitivity-placental-hypoxia-and-male-offspring-insulin-sensitivity
#15
Denise S Fernandez-Twinn, Geraldine Gascoin, Barbara Musial, Sarah Carr, Daniella Duque-Guimaraes, Heather L Blackmore, Maria Z Alfaradhi, Elena Loche, Amanda N Sferruzzi-Perri, Abigail L Fowden, Susan E Ozanne
The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28281917/brd4-inhibitor-ibet-upregulates-p27kip-cip-protein-stability-in-neuroendocrine-tumor-cells
#16
Lei Wang, Smita Matkar, Gengchen Xie, Chiying An, Xin He, Xiangchen Kong, Xiuheng Liu, Xianxin Hua
The prevalence of neuroendocrine tumors (NETs) has recently been increasing. Although various drugs such as Octreotide and its analogs show certain efficacy, NETs in many patients progress and metastasize. It is desirable to develop new interventions to improve the therapy. Here we show that human neuroendocrine tumor BON cells are resistant to several drugs commonly used for NET therapy, including Octreotide that activates somatostatin receptor-induced anti-proliferation, and Capecitabine and Temozolimide that damage DNA...
March 10, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28281439/epigenetic-phosphorylation-control-of-mycobacterium-tuberculosis-infection-and-persistence
#17
Melissa Richard-Greenblatt, Yossef Av-Gay
Reversible protein phosphorylation is the most common type of epigenetic posttranslational modification in living cells used as a major regulation mechanism of biological processes. The Mycobacterium tuberculosis genome encodes for 11 serine/threonine protein kinases that are responsible for sensing environmental signals to coordinate a cellular response to ensure the pathogen's infectivity, survival, and growth. To overcome killing mechanisms generated within the host during infection, M. tuberculosis enters a state of nonreplicating persistence that is characterized by arrested growth, limited metabolic activity, and phenotypic resistance to antimycobacterial drugs...
March 2017: Microbiology Spectrum
https://www.readbyqxmd.com/read/28276448/blood-dna-methylation-pattern-is-altered-in-mesial-temporal-lobe-epilepsy
#18
Hong-Yu Long, Li Feng, Jin Kang, Zhao-Hui Luo, Wen-Biao Xiao, Li-Li Long, Xiao-Xin Yan, Luo Zhou, Bo Xiao
Mesial temporal lobe epilepsy (MTLE) is a common epileptic disorder; little is known whether it is associated with peripheral epigenetic changes. Here we compared blood whole genomic DNA methylation pattern in MTLE patients (n = 30) relative to controls (n = 30) with the Human Methylation 450 K BeadChip assay, and explored genes and pathways that were differentially methylated using bioinformatics profiling. The MTLE and control groups showed significantly different (P < 1.03e-07) DNA methylation at 216 sites, with 164 sites involved hyper- and 52 sites hypo- methylation...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275218/epigenomic-regulation-of-androgen-receptor-signaling-potential-role-in-prostate-cancer-therapy
#19
REVIEW
Vito Cucchiara, Joy C Yang, Vincenzo Mirone, Allen C Gao, Michael G Rosenfeld, Christopher P Evans
Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome...
January 16, 2017: Cancers
https://www.readbyqxmd.com/read/28275132/impact-of-polyunsaturated-and-saturated-fat-overfeeding-on-the-dna-methylation-pattern-in-human-adipose-tissue-a-randomized-controlled-trial
#20
Alexander Perfilyev, Ingrid Dahlman, Linn Gillberg, Fredrik Rosqvist, David Iggman, Petr Volkov, Emma Nilsson, Ulf Risérus, Charlotte Ling
Background: Dietary fat composition can affect ectopic lipid accumulation and, thereby, insulin resistance. Diets that are high in saturated fatty acids (SFAs) or polyunsaturated fatty acids (PUFAs) have different metabolic responses.Objective: We investigated whether the epigenome of human adipose tissue is affected differently by dietary fat composition and general overfeeding in a randomized trial.Design: We studied the effects of 7 wk of excessive SFA (n = 17) or PUFA (n = 14) intake (+750 kcal/d) on the DNA methylation of ∼450,000 sites in human subcutaneous adipose tissue...
March 8, 2017: American Journal of Clinical Nutrition
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