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Epigenetic resistance

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https://www.readbyqxmd.com/read/29453291/lsd1-inhibition-exerts-its-anti-leukemic-effect-by-recommissioning-pu-1-and-c-ebp%C3%AE-dependent-enhancers-in-aml
#1
Monica Cusan, Sheng F Cai, Helai P Mohammad, Andrei Krivtsov, Alan Chramiec, Evangelia Loizou, Matthew D Witkin, Kimberly N Smitheman, Daniel G Tenen, Min Ye, Britta Will, Ulrich Steidl, Ryan G Kruger, Ross L Levine, Hugh Y Rienhoff, Richard P Koche, Scott A Armstrong
Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML...
February 16, 2018: Blood
https://www.readbyqxmd.com/read/29452952/phasevarions-of-bacterial-pathogens-methylomics-sheds-new-light-on-old-enemies
#2
REVIEW
John M Atack, Aimee Tan, Lauren O Bakaletz, Michael P Jennings, Kate L Seib
A wide variety of bacterial pathogens express phase-variable DNA methyltransferases that control expression of multiple genes via epigenetic mechanisms. These randomly switching regulons - phasevarions - regulate genes involved in pathogenesis, host adaptation, and antibiotic resistance. Individual phase-variable genes can be identified in silico as they contain easily recognized features such as simple sequence repeats (SSRs) or inverted repeats (IRs) that mediate the random switching of expression. Conversely, phasevarion-controlled genes do not contain any easily identifiable features...
February 13, 2018: Trends in Microbiology
https://www.readbyqxmd.com/read/29452350/extra-virgin-olive-oil-contains-a-metabolo-epigenetic-inhibitor-of-cancer-stem-cells
#3
Bruna Corominas-Faja, Elisabet Cuyàs, Jesús Lozano-Sánchez, Sílvia Cufí, Sara Verdura, Salvador Fernández-Arroyo, Isabel Borrás-Linares, Begoña Martin-Castillo, Ángel G Martin, Ruth Lupu, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Vicente Micol, Jorge Joven, Antonio Segura-Carretero, Javier A Menendez
Targeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO) capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid decarboxymethyl oleuropein aglycone (DOA) could selectively target sub-populations of epithelial-like, aldehyde dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24-/low CSC...
February 14, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29449840/c-abl-twist1-epigenetically-dysregulate-inflammatory-responses-during-mycobacterial-infection-by-co-regulating-bone-morphogenesis-protein-and-mir27a
#4
Kasturi Mahadik, Praveen Prakhar, R S Rajmani, Amit Singh, Kithiganahalli Narayanaswamy Balaji
Mycobacteria propelled modulation of host responses is of considerable interest in the face of emerging drug resistance. Although it is known that Abl tyrosine kinases affect entry and persistence of mycobacteria, mechanisms that couple c-Abl to proximal signaling pathways during immunity are poorly understood. Loss-of-function of c-Abl through Imatinib, in a mouse model of tuberculosis or RNA interference, identified bone morphogenesis protein (BMP) signaling as its cellular target. We demonstrate that c-Abl promotes mycobacterial survival through epigenetic modification brought about by KAT5-TWIST1 at Bmp loci...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29445425/mosaicism-for-gnas-methylation-defects-associated-with-pseudohypoparathyroidism-type-1b-arose-in-early-post-zygotic-phases
#5
Francesca Marta Elli, Paolo Bordogna, Maura Arosio, Anna Spada, Giovanna Mantovani
Background: Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases, with no known underlying primary genetic lesions, could represent true stochastic errors in early embryonic maintenance of methylation. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29444873/hypoxia-inducible-kdm3a-addiction-in-multiple-myeloma
#6
Sho Ikeda, Akihiro Kitadate, Fumito Abe, Naoto Takahashi, Hiroyuki Tagawa
In multiple myeloma (MM), the bone marrow (BM) microenvironment may contain a myeloma cell fraction that has acquired treatment resistance by undergoing an epigenetic gene expression change. Hypoxic stress is an important factor in the BM microenvironment. Recently, we demonstrated that miR-210 was upregulated in hypoxia and downregulated IRF4, which is known as an essential factor in myeloma oncogenesis in normoxia. In the study, we demonstrated that myeloma cells still showed a strong antiapoptotic phenotype despite IRF4 downregulation, suggesting that another antiapoptotic factor might be involved under hypoxic stress...
February 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/29440180/resistance-promoting-effects-of-ependymoma-treatment-revealed-through-genomic-analysis-of-multiple-recurrences-in-a-single-patient
#7
Christopher A Miller, Sonika Dahiya, Tiandao Li, Robert Fulton, Matthew D Smyth, Gavin P Dunn, Joshua B Rubin, Elaine R Mardis
BACKGROUND: As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pre-genomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies...
February 13, 2018: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/29436261/an-epigenomic-approach-to-identifying-differential-overlapping-and-cis-acting-lncrnas-in-cisplatin-resistant-cancer-cells
#8
Olga Vera, Carlos Rodriguez-Antolin, Javier de Castro, Florian A Karreth, Thomas A Sellers, Inmaculada Ibañez de Caceres
Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non-small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing...
February 13, 2018: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29432557/epigenetic-modifiers-as-new-immunomodulatory-therapies-in-solid-tumours
#9
S Aspeslagh, D Morel, J-C Soria, S Postel-Vinay
Background: Immune therapies have revolutionized cancer treatment over the last few years by allowing improvements in overall survival. However, the majority of patients is still primary or secondary resistant to such therapies, and enhancing sensitivity to immune therapies is therefore crucial to improve patient outcome. Several recent lines of evidence suggest that epigenetic modifiers have intrinsic immunomodulatory properties, which could be of therapeutic interest. Material and Methods: We reviewed preclinical evidence and clinical studies which describe or exploit immunomodulatory properties of epigenetic agents...
February 7, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29431644/induction-of-microrna-199-by-nitric-oxide-in-endothelial-cells-is-required-for-nitrovasodilator-resistance-via-targeting-of-prostaglandin-i2-synthase
#10
Yong-Ping Bai, Jia-Xiong Zhang, Quan Sun, Ji-Peng Zhou, Jing-Min Luo, Ling-Fang He, Xing-Chi Lin, Ling-Ping Zhu, Wan-Zhou Wu, Zhen-Yu Wang, Guo-Gang Zhang
Background -Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, owing to the dysfunction of prostaglandin I2 synthase (PTGIS). Micro RNAs (miRNAs) repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. Methods -Nitrovasodilator resistance was induced by nitroglycerin (GTN; 100 mg/kg/day, 3 days) infusion in Apoe-/- mice...
February 5, 2018: Circulation
https://www.readbyqxmd.com/read/29431643/epigenetic-dysregulation-of-the-drp1-binding-partners-mid49-and-mid51-increases-mitotic-mitochondrial-fission-and-promotes-pulmonary-arterial-hypertension-mechanistic-and-therapeutic-implications
#11
Kuang-Hueih Chen, Asish Dasgupta, Jianhui Lin, Francois Potus, Sebastien Bonnet, James Iremonger, Jennifer Fu, Jeffrey Mewburn, Danchen Wu, Kimberly Dunham-Snary, Anne L Theilmann, Zhi-Cheng Jing, Charles Hindmarch, Mark L Ormiston, Allan Lawrie, Stephen L Archer
Background -Mitotic fission is increased in pulmonary arterial hypertension (PAH), a hyperproliferative, apoptosis-resistant disease. The fission mediator, dynamin related protein 1 (Drp1) must complex with adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore their dysregulation in PAH...
February 5, 2018: Circulation
https://www.readbyqxmd.com/read/29428954/tumour-heterogeneity-of-breast-cancer-from-morphology-to-personalised-medicine
#12
Mohammed A Aleskandarany, Michel E Vandenberghe, Caterina Marchiò, Ian O Ellis, Anna Sapino, Emad A Rakha
Breast cancer (BC) displays striking clinical, morphological, and behavioural diversity within a single tumour and between tumours. Currently, mounting evidence indicates that the morphological heterogeneity of BC reflects an underlying spectrum of genetic and epigenetic portraits that control BC behaviour. Further understanding of BC heterogeneity will have an impact, not only on the routine diagnostic practices but also on patients' management decisions. Phenomena like diagnostic inconsistencies and therapeutic resistance, both primary and acquired, could be attributed, at least in part, to tumour heterogeneity within the same cancer and between the primary disease and subsequent recurrences...
February 10, 2018: Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29423902/a-novel-substrate-radiotracer-for-molecular-imaging-of-sirt2-expression-and-activity-with-positron-emission-tomography
#13
Robin E Bonomi, Maxwell Laws, Vadim Popov, Swatabdi Kamal, Shreya Potukutchi, Aleksandr Shavrin, Xin Lu, Nashaat Turkman, Ren-Shyan Liu, Thomas Mangner, Juri G Gelovani
PURPOSE: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. PROCEDURES: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716...
February 8, 2018: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/29423855/in-situ-chromatin-binding-assay-using-epifluorescent-microscopy-in-s-pombe
#14
Jinpu Yang, Fei Li
Chromatin-associated proteins play critical roles in many cellular processes, including gene expression, epigenetic regulation, DNA repair, recombination, and replication. Especially, epigenetic landscape, shaped by a variety of chromatin-binding proteins, is dynamic and regulated in a context-dependent manner. In situ chromatin-binding assay is a powerful but simple tool to investigate how proteins, such as epigenetic components, associate with chromatin. This approach relies on the fact that chromatin bound proteins are more resistant to detergent extraction...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29422611/decitibine-improve-the-efficiency-of-anti-pd-1-therapy-via-activating-the-response-to-ifn-pd-l1-signal-of-lung-cancer-cells
#15
Qi Lai, Haiyong Wang, Angui Li, Yinhui Xu, Liang Tang, Qiang Chen, Chunfang Zhang, Yang Gao, Jianfei Song, Zhenzong Du
IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation...
February 9, 2018: Oncogene
https://www.readbyqxmd.com/read/29421999/dna-double-strand-break-repair-related-synthetic-lethality
#16
Monika Toma, Tomasz Skorski, Tomasz Sliwinski
Cancer is a heterogeneous disease with a high degree of diversity between and within tumors. Our limited knowledge of their biology results in ineffective treatment. However, personalized approach may represent a milestone in the field of anticancer therapy. It can increase specificity of treatment against tumor initiating cancer stem cells (CSCs) and cancer progenitor cells (CPCs) with minimal effect on normal cells and tissues. Cancerous cells carry multiple genetic and epigenetic aberrations which may disrupt pathways essential for cell survival...
January 31, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29418079/concise-review-chronic-myeloid-leukemia-stem-cell-niche-and-response-to-pharmacologic-treatment
#17
REVIEW
Elena Arrigoni, Marzia Del Re, Sara Galimberti, Giuliana Restante, Eleonora Rofi, Stefania Crucitta, Claudia Baratè, Mario Petrini, Romano Danesi, Antonello Di Paolo
Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog...
February 8, 2018: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/29416873/biomarker-discovery-for-renal-cancer-stem-cells
#18
REVIEW
Claudia Corrò, Holger Moch
Characterised by high intra- and inter-tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo- and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self-renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence...
January 2018: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/29416701/exploring-the-molecular-aspects-associated-with-testicular-germ-cell-tumors-a-review
#19
REVIEW
Gaetano Facchini, Sabrina Rossetti, Carla Cavaliere, Carmine D'Aniello, Rossella Di Franco, Gelsomina Iovane, Giovanni Grimaldi, Raffaele Piscitelli, Paolo Muto, Gerardo Botti, Sisto Perdonà, Bianca Maria Veneziani, Massimiliano Berretta, Micaela Montanari
Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recent preclinical data regarding biological signaling machinery as well as genetic and epigenetic mechanisms associated with molecular patterns of tumors have contribute to explain the pathogenesis and the differentiation of TGCTs and to understand the mechanisms responsible for the development of resistance to treatment...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29415999/microrna-27a-5p-regulation-by-promoter-methylation-and-myc-signaling-in-prostate-carcinogenesis
#20
Daniela Barros-Silva, Pedro Costa-Pinheiro, Henrique Duarte, Elsa Joana Sousa, Adriane Feijó Evangelista, Inês Graça, Isa Carneiro, Ana Teresa Martins, Jorge Oliveira, André L Carvalho, Márcia M Marques, Rui Henrique, Carmen Jerónimo
Upregulation of MYC and miRNAs deregulation are common in prostate cancer (PCa). Overactive MYC may cause miRNAs' expression deregulation through transcriptional and post-transcriptional mechanisms and epigenetic alterations are also involved in miRNAs dysregulation. Herein, we aimed to elucidate the role of regulatory network between MYC and miRNAs in prostate carcinogenesis. MYC expression was found upregulated in PCa cases and matched precursor lesions. MicroRNA's microarray analysis of PCa samples with opposed MYC levels identified miRNAs significantly overexpressed in high-MYC PCa...
February 7, 2018: Cell Death & Disease
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