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https://www.readbyqxmd.com/read/28342984/hdac4-and-hdac6-sustain-dna-double-strand-break-repair-and-stem-like-phenotype-by-promoting-radioresistance-in-glioblastoma-cells
#1
Francesco Marampon, Francesca Megiorni, Simona Camero, Clara Crescioli, Heather P McDowell, Roberta Sferra, Antonella Vetuschi, Simona Pompili, Luca Ventura, Francesca De Felice, Vincenzo Tombolini, Carlo Dominici, Roberto Maggio, Claudio Festuccia, Giovanni Luca Gravina
The role of histone deacetylase (HDAC) 4 and 6 in glioblastoma (GBM) radioresistance was investigated. We found that tumor samples from 31 GBM patients, who underwent temozolomide and radiotherapy combined treatment, showed HDAC4 and HDAC6 expression in 93.5% and 96.7% of cases, respectively. Retrospective clinical data analysis demonstrated that high-intensity HDAC4 and/or HDAC6 immunostaining was predictive of poor clinical outcome. In vitro experiments revealed that short hairpin RNA-mediated silencing of HDAC4 or HDAC6 radiosensitized U87MG and U251MG GBM cell lines by promoting DNA double-strand break (DSBs) accumulation and by affecting DSBs repair molecular machinery...
March 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28337317/structural-requirements-of-hdac-inhibitors-saha-analogues-modified-at-the-c2-position-display-hdac6-8-selectivity
#2
Ahmed T Negmeldin, Geetha Padige, Anton V Bieliauskas, Mary Kay H Pflum
Histone deacetylase (HDAC) proteins are epigenetic regulators that deacetylate protein substrates, leading to subsequent changes in cell function. HDAC proteins are implicated in cancers, and several HDAC inhibitors have been approved by the FDA as anticancer drugs, including SAHA (suberoylanilide hydroxamic acid; Vorinostat and Zolinza). Unfortunately, SAHA inhibits most HDAC isoforms, which limits its use as a pharmacological tool and may lead to side effects in the clinic. In this work SAHA analogues substituted at the C2 position were synthesized and screened for HDAC isoform selectivity in vitro and in cells...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28332438/quantitative-structure-activity-relationship-analysis-and-virtual-screening-studies-for-identifying-hdac2-inhibitors-from-known-hdac-bioactive-chemical-libraries
#3
H Pham-The, G Casañola-Martin, K Diéguez-Santana, N Nguyen-Hai, N T Ngoc, L Vu-Duc, H Le-Thi-Thu
Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0...
March 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28321036/a-highly-potent-and-selective-histone-deacetylase-6-inhibitor-prevents-dss-induced-colitis-in-mice
#4
Ting Liu, Renping Wang, Haojie Xu, Yunlong Song, Yunpeng Qi
Inflammatory bowel disease (IBD) is a refractory illness with remarkably increasing incidence rate all over the world. However, no desirable treatment scheme is available. Therefore, research and development of new drugs for treating IBD are urgently needed. Histone deacetylase 6 (HDAC6) is considered to be a pro-inflammatory factor, thus the inhibitors specifically-targeting HDAC6 may find their way in IBD treatment. In this study, we evaluated the anti-inflammatory activity of a novel potent and selective HDAC6 inhibitor, LTB2, in dextran sulfate sodium (DSS)-induced colitis mouse model...
March 17, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28315173/ricolinostat-a-selective-hdac6-inhibitor-shows-anti-lymphoma-cell-activity-alone-and-in-combination-with-bendamustine
#5
Maria Cosenza, Monica Civallero, Luigi Marcheselli, Stefano Sacchi, Samantha Pozzi
Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry...
March 17, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28287402/hdac6-mediated-acetylation-of-lipid-droplet-binding-protein-cidec-regulates-fat-induced-lipid-storage
#6
Hui Qian, Yuanying Chen, Zongqian Nian, Lu Su, Haoyong Yu, Feng-Jung Chen, Xiuqin Zhang, Wenyi Xu, Linkang Zhou, Jiaming Liu, Jinhai Yu, Luxin Yu, Yan Gao, Hongchao Zhang, Haihong Zhang, Shimin Zhao, Li Yu, Rui-Ping Xiao, Yuqian Bao, Shaocong Hou, Pingping Li, Jiada Li, Haiteng Deng, Weiping Jia, Peng Li
Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans. Mice with adipocyte-specific depletion of Hdac6 exhibited increased fat accumulation and reduced insulin sensitivity. In normal adipocytes, we found that reversal of P300/CBP-associated factor-induced (PCAF-induced) acetylation at K56 on cell death-inducing DFFA-like effector C (CIDEC, also known as FSP27) critically regulated lipid droplet fusion and lipid storage...
March 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28273454/map3k4-controls-the-chromatin-modifier-hdac6-during-trophoblast-stem-cell-epithelial-to-mesenchymal-transition
#7
Robert J Mobley, Deepthi Raghu, Lauren D Duke, Kayley Abell-Hart, Jon S Zawistowski, Kyla Lutz, Shawn M Gomez, Sujoy Roy, Ramin Homayouni, Gary L Johnson, Amy N Abell
The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TS(KI4) cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28271209/tgf-%C3%AE-1-impairs-mechanosensation-of-human-osteoblasts-via-hdac6-mediated-shortening-and-distortion-of-primary-cilia
#8
Sabrina Ehnert, Vrinda Sreekumar, Romina H Aspera-Werz, Sahar O Sajadian, Elke Wintermeyer, Gunther H Sandmann, Christian Bahrs, Jan G Hengstler, Patricio Godoy, Andreas K Nussler
Transforming growth factor β (TGF-β) is a critical regulator of bone density owing to its multiple effects on cell growth and differentiation. Recently, we have shown that TGF-β1 effectively blocks bone morphogenetic protein (BMP) induced maturation of osteoblasts by upregulating histone deacetylase (HDAC) activity. The current study aimed at investigating the effect of rhTGF-β1 treatment on the expression of specific HDACs and their cellular effects, e.g., microtubule structures (primary cilia) and mechanosensation...
March 7, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28267067/hdac6-inhibition-effectively-reverses-chemotherapy-induced-peripheral-neuropathy
#9
Karen Krukowski, Jiacheng Ma, Olga Golonzhka, Geoffroy O Laumet, Tanuja Gutti, John H van Duzer, Ralph Mazitschek, Matthew B Jarpe, Cobi J Heijnen, Annemieke Kavelaars
Chemotherapy-induced peripheral neuropathy is one of the most common doselimiting side-effects of cancer treatment. Currently, there is no FDA-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of á-tubulin-dependent intracellular mitochondrial transport. Here we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 versus other HDACs...
March 4, 2017: Pain
https://www.readbyqxmd.com/read/28264055/enhancement-of-pomalidomide-anti-tumor-response-with-acy-241-a-selective-hdac6-inhibitor
#10
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
https://www.readbyqxmd.com/read/28241840/increased-acetylation-of-peroxiredoxin1-by-hdac6-inhibition-leads-to-recovery-of-a%C3%AE-induced-impaired-axonal-transport
#11
Heesun Choi, Haeng Jun Kim, Jisoo Kim, Soohyun Kim, Jinhee Yang, Wonik Lee, Yeonju Park, Seung Jae Hyeon, Dong-Sup Lee, Hoon Ryu, Junho Chung, Inhee Mook-Jung
BACKGROUND: Reduction or inhibition of histone deacetylase 6 (HDAC6) has been shown to rescue memory in mouse models of Alzheimer's disease (AD) and is recently being considered a possible therapeutic strategy. However, the restoring mechanism of HDAC6 inhibition has not been fully understood. METHODS AND RESULTS: Here, we found that an anti-oxidant protein Peroxdiredoxin1 (Prx1), a substrate of HDAC6, malfunctions in Aβ treated cells, the brains of 5xFAD AD model mice and AD patients...
February 28, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28222070/inhibition-of-polypyrimidine-tract-binding-protein-3-induces-apoptosis-and-cell-cycle-arrest-and-enhances-the-cytotoxicity-of-5-fluorouracil-in-gastric-cancer-cells
#12
Xin Liang, Haiyang Shi, Liyan Yang, Cen Qiu, Shengchao Lin, Yingxue Qi, Jiyu Li, Aiguang Zhao, Jianwen Liu
BACKGROUND: Human polypyrimidine tract binding protein 3 (PTBP3) was first discovered in 1999 and has been well characterised as a differentiation regulator. However, its role in human cancer has rarely been reported. Our previous study revealed increased PTBP3 protein level in gastric cancer tissues. Downregulation of PTBP3 suppressed the proliferation and differentiation of gastric cancer cells in vivo. METHODS: PTBP3 mRNA levels in human gastric cancer and adjuvant non-tumour tissues were detected...
February 21, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28215142/small-molecule-modulation-of-hdac6-activity-the-propitious-therapeutic-strategy-to-vanquish-neurodegenerative-disorders
#13
Shabir Ahmad Ganai
Histone deacetylases (HDACs) are epigenetic enzymes creating the transcriptionally inactive state of chromatin by erasing acetyl moiety from histone and non-histone substrates. HDAC6 modulates several biological pathways in dividing cells as well as in post-mitotic neurons, and has been implicated in the pathophysiology of neurodegeneration. The distinct cellular functions and survival in these cells are reliant on HDAC6-mediated processes including intracellular trafficking, chaperone-mediated stress responses, anti-oxidation and protein degradation...
February 8, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28214844/autophagy-activation-by-rapamycin-before-hypoxia-reoxygenation-reduces-endoplasmic-reticulum-stress-in-alveolar-epithelial-cells
#14
Tao Fan, Lei Chen, Zhixin Huang, Wei Wang, Boyou Zhang, Yao Xu, Zhangfan Mao, Hao Hu, Qing Geng
BACKGROUND: To determine potential effects of autophagy activation on hypoxia-reoxygenation (H/R) induced damage of a rat alveolar epithelial cell line. METHODS: CCL149 cells were subjected to autophagy agonist (rapamycin, Rap), autophagy inhibitor (3-methyladenine, 3-MA) or PBS for 1 h before H/R treatment for 2 h, 4 h and 6 h. The optimal concentration of Rap (150 nM, 200 nM and 250 nM) or 3-MA (5 mM, 10 mM and 15 mM) was obtained from MTT assay. Autophagy was determined by fluorescence microscopy of eRFP-LC3 positive cells, transmission electron microscopy of autophagosome, western blot of LC3, AMPK, Beclin-1, HDAC6 and p62 proteins...
January 17, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28213282/design-synthesis-and-biological-evaluation-of-thienopyrimidine-hydroxamic-acid-based-derivatives-as-structurally-novel-histone-deacetylase-hdac-inhibitors
#15
Jiang Wang, Mingbo Su, Tingting Li, Anhui Gao, Wei Yang, Li Sheng, Yi Zang, Jia Li, Hong Liu
New thienopyrimidine hydroxamic acid derivatives as HDACs inhibitors were designed, synthesized and evaluated. All compounds were evaluated for their ability to inhibit recombinant human HDAC1, HDAC3, and HDAC6 isoforms and in vitro anti-proliferative activity on tumor cell lines RMPI 8226 and HCT 116. Most of these compounds displayed good to excellent inhibitory activities against HDACs. The IC50 values of compound 9m against HDAC1, HDAC3, and HDAC6 was 29.81 ± 0.52 nM, 24.71 ± 1.16 nM, and 21.29 ± 0...
January 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28195408/microrna-22-promoted-osteogenic-differentiation-of-human-periodontal-ligament-stem-cells-by-targeting-hdac6
#16
Guang-Qi Yan, Xue Wang, Fan Yang, Min-Liang Yang, Guo-Kun Wang, Qing Zhou
Stem cells transplantation is a promising therapy strategy for accelerating periodontal regeneration and reconstruction. Genetic modification could induce stem cells directional differentiation to facilitate recovery of physiological functions. In this study, we investigated the role and mechanism of miR-22 on human periodontal ligament stem cells (PDLSCs). Firstly, a cellular model of osteogenic differentiation was first established by osteogenic inductive cocktail. Real-time PCR determined that expression of miR-22 was significantly increased during PDLSCs osteogenic differentiation...
February 13, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28188215/cystathionine-gamma-lyase-protects-vascular-endothelium-a-role-for-inhibition-of-histone-deacetylase-6
#17
Thorsten Martin Leucker, Yohei Nomura, Jae Hyung Kim, Anil Bhatta, Victor Wang, Andrea Wecker, Sandeep S Jandu, Lakshmi Santhanam, Dan E Berkowitz, Lewis Romer, Deepesh Pandey
Endothelial cystathionine -lyase (CSE) contributes to cardiovascular homeostasis, mainly through production of hydrogen sulfide. However, the molecular mechanisms that control CSE gene expression in endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDAC) in the regulation of endothelial CSE. Reduced CSE mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to OxLDL and in aortas from atherogenic ApoE-/- mice fed a high-fat diet as compared with controls...
February 10, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28178513/the-role-of-histone-deacetylase-6-in-synaptic-plasticity-and-memory
#18
Sarah Perry, Beril Kiragasi, Dion Dickman, Anandasankar Ray
Histone deacetylases (HDACs) have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogaster and found memory deficits with RPD3 and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6 rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC) domain is required for this ability...
February 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28153791/hdac6-deacetylates-p53-at-lysines-381-382-and-differentially-coordinates-p53-induced-apoptosis
#19
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Junjeong Choi, Gyoonhee Han, Kang Young Lee, So Hee Kwon
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation...
January 30, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28131906/a-novel-hdac6-inhibitor-tubastatin-a-controls-hdac6-p97-vcp-mediated-ubiquitination-autophagy-turnover-and-reverses-temozolomide-induced-er-stress-tolerance-in-gbm-cells
#20
Zong-Yang Li, Ce Zhang, Yuan Zhang, Lei Chen, Bao-Dong Chen, Qing-Zhong Li, Xie-Jun Zhang, Wei-Ping Li
Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells...
January 26, 2017: Cancer Letters
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