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https://www.readbyqxmd.com/read/28737768/arid1a-mutated-ovarian-cancers-depend-on-hdac6%C3%A2-activity
#1
Benjamin G Bitler, Shuai Wu, Pyoung Hwa Park, Yang Hai, Katherine M Aird, Yemin Wang, Yali Zhai, Andrew V Kossenkov, Ana Vara-Ailor, Frank J Rauscher Iii, Weiping Zou, David W Speicher, David G Huntsman, Jose R Conejo-Garcia, Kathleen R Cho, David W Christianson, Rugang Zhang
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours...
July 24, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28735518/the-possible-prognostic-role-of-histone-deacetylase-and-transforming-growth-factor-%C3%AE-smad-signaling-in-high-grade-gliomas-treated-by-radio-chemotherapy-a-preliminary-immunohistochemical-study
#2
Roberta Sferra, Simona Pompili, Claudio Festuccia, Francesco Marampon, Giovanni L Gravina, Luca Ventura, Ernesto Di Cesare, Sara Cicchinelli, Eugenio Gaudio, Antonella Vetuschi
Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system. Unfortunately, patients affected by this disease have a very poor prognosis, due to high level of invasiveness and resistance to standard therapies. Although the molecular profile of GBM has been extensively investigated, the events responsible for its pathogenesis and progression remain largely unknown. Histone Deacetylases (HDAC) dependent epigenetic modifications and transforming growth factor (TGF)-β/Smad pathway seem to play an important role in GBM tumorigenesis, resistance to common therapies and poor clinical outcome...
May 16, 2017: European Journal of Histochemistry: EJH
https://www.readbyqxmd.com/read/28710961/epigenetic-modification-differences-between-fetal-fibroblast-cells-and-mesenchymal-stem-cells-of-the-arbas-cashmere-goat
#3
Xiao Wang, Zhimin Wang, Qing Wang, Hefei Wang, Hao Liang, Dongjun Liu
To explore the epigenetic mechanisms regulating mesenchymal stem cells, we analyzed epigenetic patterns in control goat fetal fibroblast cells (gFFCs), adipose-derived stem cells (gADSCs), bone marrow stromal cells (gBMSCs), and muscle-derived satellite cells (gMDSCs). We found that the 5mC content of gBMSC genomes was lower than that of gFFC genomes, while the 5mC content of gADSC and gMDSC genomes surpassed that of gFFC genomes. H3K9 acetylation did not differ significantly among those cells; gFFCs, gADSCs, and gMDSCs contained acetylated H3K9, H3K14, H3K18, H4K5, and H4K12, but gBMSCs contained almost no acetylated H4K5 and H4K12...
July 9, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28708596/hdac6-inhibitor-wt161-downregulates-growth-factor-receptors-in-breast-cancer
#4
Teru Hideshima, Ralph Mazitschek, Jun Qi, Naoya Mimura, Jen-Chieh Tseng, Andrew L Kung, James E Bradner, Kenneth C Anderson
We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700998/a-decrease-of-histone-deacetylase-6-expression-caused-by-helicobacter-pylori-infection-is-associated-with-oncogenic-transformation-in-gastric-cancer
#5
Qing He, Guoqiang Li, Xin Wang, Shubin Wang, Jiang Hu, Lang Yang, Yuqi He, Yuanming Pan, Dedong Yu, Yun Wu
BACKGROUND: Histone deacetylase 6 (HDAC6) plays a role in the progression of many tumors. However, the relationship between the level of HDAC6 expression and gastric tumorigenesis is still unclear. Here, we illustrate the potential correlation between Helicobacter pylori (HP) infection and the variation of HDAC6 expression in different gastric lesions, as well as the clinical significance of HDAC6 expression in gastric cancer (GC) patients. MATERIALS AND METHODS: Between 2011 and 2016, 364 patients with different types of gastric lesions were enrolled in Baotou City Central Hospital...
July 13, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28681565/tubulin-acetylation-a-novel-functional-avenue-for-cdyl-in-sperm
#6
Sweta Parab, Veena Dalvi, Sushma Mylavaram, Abhipriya K, Susan Idicula-Thomas, Shobha Sonawane, Priyanka Parte
Motility in sperm is driven by the flagella, the principal component of which is the axoneme. The microtubules which make up the 9 + 2 axoneme are composed of heterodimers of alpha and beta tubulins and undergo several post-translational modifications. We have earlier reported that HDAC6 functions as tubulin deacetylase in sperm and has a role in sperm movement. While exploring the specific tubulin acetyltransferase (TAT) in sperm we observed the presence of Chromodomain Y-Like (CDYL), on the principal piece of rat spermatozoa which compelled us to explore its function in sperm...
July 6, 2017: Cytoskeleton
https://www.readbyqxmd.com/read/28674407/hdac6-a-novel-histone-deacetylase-implicated-in-pulmonary-arterial-hypertension
#7
Olivier Boucherat, Sophie Chabot, Roxane Paulin, Isabelle Trinh, Alice Bourgeois, François Potus, Marie-Claude Lampron, Caroline Lambert, Sandra Breuils-Bonnet, Valérie Nadeau, Renée Paradis, Elena A Goncharova, Steeve Provencher, Sébastien Bonnet
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a "cancer-like" pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH...
July 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28673326/therapeutic-effect-of-a-novel-histone-deacetylase-6-inhibitor-ckd-l-on-collagen-induced-arthritis-in-vivo-and-regulatory-t-cells-in-rheumatoid-arthritis-in-vitro
#8
Bo Ram Oh, Dong-Hyeon Suh, Daekwon Bae, Nina Ha, Young Il Choi, Hyun Jung Yoo, Jin Kyun Park, Eun Young Lee, Eun Bong Lee, Yeong Wook Song
BACKGROUND: Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA). METHODS: CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days...
July 3, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28668087/inhibition-of-hdac6-activity-through-interaction-with-ranbpm-and-its-associated-ctlh-complex
#9
Louisa M Salemi, Matthew E R Maitland, Eyal R Yefet, Caroline Schild-Poulter
BACKGROUND: Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase that promotes many cellular processes that lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) and HDAC6 and found that RanBPM expression inhibits HDAC6 activity. RanBPM is part of a putative E3 ubiquitin ligase complex, termed the C-terminal to LisH (CTLH) complex. Here, we investigated the involvement of the CTLH complex on HDAC6 inhibition and assessed the outcome of this regulation on the cellular motility induced by HDAC6...
July 1, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28648461/the-structural-requirements-of-histone-deacetylase-inhibitors-saha-analogs-modified-at-the-c5-position-display-dual-hdac6-8-selectivity
#10
Ahmed T Negmeldin, Mary Kay H Pflum
Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28648015/-therapeutic-effects-of-tubastatin-a-hcl-on-airway-inflammation-in-acute-mice-asthma-model
#11
X M Su, Y Ren, M L Li, X Zhao, J Kang
Objective: To investigated the therapeutic effects of Tubastatin A Hcl, a selective HDAC6 inhibitor, on airway inflammation in acute mice bronchial asthma (asthma) model. Methods: A total of 48 BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and Tubastatin A Hcl group with 12 mice in each group. Then the airway hyperresponsiveness was assessed in each group; total cell number, different cell number, levels of Interleukin (IL)-4, IL-5 and Interferon-γ (IFN-γ) in the bronchoalveolar lavage fluid (BALF) were detected; the lung tissues of each group were stained with HE to observe the inflammatory cells infiltration...
June 27, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28636534/novel-tropolones-induce-the-unfolded-protein-response-pathway-and-apoptosis-in-multiple-myeloma-cells
#12
Staci L Haney, Cheryl Allen, Michelle L Varney, Kaitlyn M Dykstra, Eric R Falcone, Sean H Colligan, Qiang Hu, Alyssa M Aldridge, Dennis L Wright, Andrew J Wiemer, Sarah A Holstein
Tropolones are small organic compounds with metal-directing moieties. Tropolones inhibit the proliferation of cancer cell lines, possibly through their effects on metalloenzymes such as select histone deacetylases (HDACs). Pan-HDAC inhibitors are therapeutically beneficial in the treatment of multiple myeloma, however there is interest in the use of more selective HDAC inhibitor therapy to minimize adverse side effects. We hypothesized that tropolones might have anti-myeloma activities. To this end, a series of novel α-substituted tropolones were evaluated for effects on multiple myeloma cells...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634388/mito-xenophagic-killing-of-bacteria-is-coordinated-by-a-metabolic-switch-in-dendritic-cells
#13
Nadine Radomski, Danny Kägebein, Elisabeth Liebler-Tenorio, Axel Karger, Elke Rufer, Birke Andrea Tews, Stefanie Nagel, Rebekka Einenkel, Anne Müller, Annica Rebbig, Michael R Knittler
Chlamydiae are bacterial pathogens that grow in vacuolar inclusions. Dendritic cells (DCs) disintegrate these compartments, thereby eliminating the microbes, through auto/xenophagy, which also promotes chlamydial antigen presentation via MHC I. Here, we show that TNF-α controls this pathway by driving cytosolic phospholipase (cPLA)2-mediated arachidonic acid (AA) production. AA then impairs mitochondrial function, which disturbs the development and integrity of these energy-dependent parasitic inclusions, while a simultaneous metabolic switch towards aerobic glycolysis promotes DC survival...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28629630/design-synthesis-and-tumor-cell-growth-inhibitory-activity-of-3-nitro-2h-cheromene-derivatives-as-histone-deacetylaes-inhibitors
#14
Shuai Tan, Feng He, Tingting Kong, Jingde Wu, Zhaopeng Liu
As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275...
June 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28628306/lysine-deacetylation-by-hdac6-regulates-the-kinase-activity-of-akt-in-human-neural-progenitor-cells
#15
Jonathan Iaconelli, Jasmin Lalonde, Bradley Watmuff, Bangyan Liu, Ralph Mazitschek, Stephen J Haggarty, Rakesh Karmacharya
The AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), and β-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1)...
July 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28623308/improved-growth-patterns-in-cystic-fibrosis-mice-after-loss-of-histone-deacetylase-6
#16
Sharon M Rymut, Deborah A Corey, Dana M Valerio, Bernadette O Erokwu, Chris A Flask, Thomas J Kelley, Craig A Hodges
Growth failure in cystic fibrosis (CF) patients has been well-documented and shown to correlate with poorer disease outcomes. This observation is also true in CF animal models, including mouse, pig, rat, and ferret. The etiology underlying growth deficits is unknown, and our previous work demonstrated reduced tubulin acetylation in CF cell models and tissue that is correctable by inhibition of histone deacetylase-6 (HDAC6). Here, we hypothesize that loss of HDAC6 will improve growth phenotype in a CF mouse model...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28599312/cullin-3spop-ubiquitin-e3-ligase-promotes-the-poly-ubiquitination-and-degradation-of-hdac6
#17
Yuyong Tan, Yanpeng Ci, Xiangpeng Dai, Fei Wu, Jianping Guo, Deliang Liu, Brian J North, Jirong Huo, Jinfang Zhang
The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines...
May 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28598228/hdac6-inhibition-disrupts-maturational-progression-and-meiotic-apparatus-assembly-in-mouse-oocytes
#18
Li Ling, Feifei Hu, Xiaoyan Ying, Juan Ge, Qiang Wang
Histone deacetylases (HDACs) have been implicated in diverse biological processes including transcriptional regulation, signal transduction, and developmental control. However, the role of HDAC6 in mammalian oocytes remains unknown. In the present study, by employing Tubastatin A (TubA), a selective HDAC6 inhibitor, we examined the effects of HDAC6 on maturational progression and meiotic apparatus in mouse oocytes. We found that HDAC6 inhibition results in maturation arrest and disruption of spindle morphology and chromosome alignment...
June 9, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28590932/tdp-43-hdac6-axis-promoted-tumor-progression-and-regulated-nutrient-deprivation-induced-autophagy-in-glioblastoma
#19
Tzu-Wei Lin, Ming-Teh Chen, Liang-Tin Lin, Pin-I Huang, Wen-Liang Lo, Yi-Ping Yang, Kai-Hsi Lu, Yi-Wei Chen, Shih-Hwa Chiou, Cheng-Wen Wu
Glioblastoma Multiforme (GBM) is a lethal primary brain tumor with poor survival lifespan and dismal outcome. Surgical resection of GBM is greatly limited due to the biological significance of brain, giving rise to tumor relapse in GBM patients. Transactive response DNA binding protein-43 (TDP-43) is a DNA/RNA-binding protein known for causing neurodegenerative diseases through post-translational modification; but little is known about its involvement in cancer development. In this study, we found that nutrient deprivation in GBM cell lines elevated TDP-43 expression by a mechanism of evasion from ubiquitin-dependent proteolytic pathway, and subsequently activated the autophagy process...
May 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28586053/hdac6-inhibition-suppresses-chondrosarcoma-by-restoring-the-expression-of-primary-cilia
#20
Wei Xiang, Fengjing Guo, Weiting Cheng, Jiaming Zhang, Junming Huang, Rui Wang, Zhongxi Ma, Kai Xu
Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6...
June 2, 2017: Oncology Reports
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