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Sriya Bhattacharya, Bandhan Mukherjee, Jules J E Doré, Qi Yuan, Carolyn W Harley, John H McLean
Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24-h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d...
October 2017: Learning & Memory
Tzu-Wei Lin, Ming-Teh Chen, Liang-Ting 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...
August 22, 2017: Oncotarget
Lubica Skultetyova, Kseniya Ustinova, Zsofia Kutil, Zora Novakova, Jiri Pavlicek, Jana Mikesova, Dalibor Trapl, Petra Baranova, Barbora Havlinova, Martin Hubalek, Zdenek Lansky, Cyril Barinka
Human histone deacetylase 6 (HDAC6) is the major deacetylase responsible for removing the acetyl group from Lys40 of α-tubulin (αK40), which is located lumenally in polymerized microtubules. Here, we provide a detailed kinetic analysis of tubulin deacetylation and HDAC6/microtubule interactions using individual purified components. Our data unequivocally show that free tubulin dimers represent the preferred HDAC6 substrate, with a K M value of 0.23 µM and a deacetylation rate over 1,500-fold higher than that of assembled microtubules...
September 14, 2017: Scientific Reports
Sara Ota, Zi-Qiang Zhou, Megan P Romero, Guang Yang, Peter J Hurlin
No abstract text is available yet for this article.
September 15, 2017: Human Molecular Genetics
Murali K Yanda, Qiangni Liu, Valeriu Cebotaru, William B Guggino, Liudmila Cebotaru
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive en-largement of multiple renal cysts, often leading to renal failure which cannot be prevented by an current treatment. Two proteins encoded by two genes are associated with ADPKD, PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD but the molecular mechanism is unresolved. Here we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that in-hibiting HDAC6 might help manage ADPKD...
September 8, 2017: Journal of Biological Chemistry
Jingjing Ren, Xiaofeng Liao, Miranda D Vieson, Miao Chen, Reilly Scott, Jillian Kazmierczak, Xin M Luo, Christopher M Reilly
We have previously demonstrated that HDAC6 expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) NZB/W F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for five weeks...
September 6, 2017: Clinical and Experimental Immunology
Stefani N Thomas, Lijun Chen, Yang Liu, Naseruddin Höti, Hui Zhang
Approximately 20% of high-grade serous ovarian cancers are homologous-recombination (HR)-deficient due to genetic and epigenetic mutations of HR pathway genes including the tumor suppressor genes BRCA1 and 2. HR deficiency (HRD) compromises cells' ability to efficiently repair DNA damage, but it also increases sensitivity to chemotherapeutic treatment strategies; however, not all ovarian cancer patients with HRD tumors exhibit positive responses to chemotherapy. Our previous iTRAQ-based comprehensive proteomic characterization of high-grade serous ovarian carcinomas found that lower levels of histone H4 acetylation at Lys12 and Lys16 (H4-K12acK16ac) were associated with HRD tumors compared with non-HRD tumors...
September 14, 2017: Journal of Proteome Research
María Galindo-Moreno, Servando Giráldez, Carmen Sáez, Miguel Á Japón, Maria Tortolero, Francisco Romero
Cyclin-dependent kinase 1 (CDK1) is the central mammalian regulator of cell proliferation and a promising therapeutic target for breast cancer. In fact, CDK1 inhibition downregulates survival and induces apoptosis. Due to its essential role, CDK1 expression and activity are strictly controlled at various levels. We previously described that CDK1 stability is also regulated and that SCF(βTrCP) ubiquitinates CDK1, which is degraded via the lysosomal pathway. In addition, in breast tumors from patients, we found a negative correlation between CDK1 accumulation and βTrCP levels, and a positive correlation with the degree of tumor malignancy...
August 30, 2017: Scientific Reports
Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B Meeker, Todd J Cohen
The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology...
August 29, 2017: Cell Reports
Hanqing He, Jiajia Wang, Ting Liu
Replication protein A (RPA) is a multifunctional, single-stranded DNA-binding protein complex and plays a critical role in DNA replication and damage response. Herein, we show that the 70-kDa subunit of RPA (RPA1) is acetylated on lysine 163 by the acetyltransferases GCN5 and PCAF and that such acetylation is reversed principally via the action of the deacetylase HDAC6. UV irradiation promotes cytoplasmic translocation of HDAC6, thereby disrupting the interaction of HDAC6 with RPA1 and increasing RPA1 acetylation...
August 29, 2017: Cell Reports
Meimei Zhao, Rui Geng, Xiang Guo, Ruoshi Yuan, Xiao Zhou, Yanyan Zhong, Yanfei Huo, Mei Zhou, Qinjian Shen, Yinglu Li, Weiguo Zhu, Jiadong Wang
The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway...
August 29, 2017: Cell Reports
Nicholas J Porter, David W Christianson
Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the α,β-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 Å resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis...
September 15, 2017: ACS Chemical Biology
Mikel Allende, Eva Molina, Ramón Lecumberri, Juan Antonio Sanchez-Arias, Ana Ugarte, Elizabeth Guruceaga, Julen Oyarzabal, José Hermida
Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression...
August 30, 2017: Thrombosis and Haemostasis
Taha Y Taha, Shaimaa M Aboukhatwa, Rachel C Knopp, Naohiko Ikegaki, Hazem Abdelkarim, Jayaprakash Neerasa, Yunlong Lu, Raghupathi Neelarapu, Thomas W Hanigan, Gregory R J Thatcher, Pavel A Petukhov
Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively...
August 10, 2017: ACS Medicinal Chemistry Letters
Malgorzata Bobrowicz, Michal Dwojak, Beata Pyrzynska, Joanna Stachura, Angelika Muchowicz, Elise Berthel, Nicole Dalla Venezia, Mieszko Kozikowski, Marta Siernicka, Nina Miazek, Piotr Zapala, Antoni Domagala, Kamil Bojarczuk, Agata Malenda, Joanna Barankiewicz, Agnieszka Graczyk-Jarzynka, Agnieszka Zagozdzon, Magdalena Gabrysiak, Jean-Jacques Diaz, Marta Karp, Ewa Lech-Maranda, Malgorzata Firczuk, Krzysztof Giannopoulos, Dimitar G Efremov, Luca Laurenti, Dunja Baatout, Lukas Frenzel, Agata Malinowska, Mikolaj Slabicki, Thorsten Zenz, Abdessamad Zerrouqi, Jakub Golab, Magdalena Winiarska
Down-regulation of CD20, a molecular target for monoclonal antibodies, is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with non-selective histone deacetylase inhibitors (HDACi). Since the use of pan-HDACi is associated with substantial side effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance...
August 22, 2017: Blood
Claudia A Simões-Pires, Vincent Zwick, Sylvian Cretton, Muriel Cuendet
The search for new histone deacetylase (HDAC) inhibitors is of increasing interest in drug discovery. Isoform selectivity has been in the spotlight since the approval of romidepsin, a class I HDAC inhibitor for cancer therapy, and the clinical investigation of HDAC6-specific inhibitors for multiple myeloma. The present method is used to determine the inhibitory activity of test compounds on HDAC1 and HDAC6 in cells. The isoform activity is measured using the ultra-high-performance liquid chromatography - mass spectrometry (UHPLC-MS) analysis of specific substrates incubated with treated and untreated HeLa cells...
August 10, 2017: Journal of Visualized Experiments: JoVE
Maria Domenica Sanna, Luca Guandalini, Maria Novella Romanelli, Nicoletta Galeotti
Current analgesic therapies for treatment of neuropathic pain are unsatisfactory. Neuropathic pain is, therefore, undertreated and there is a significant need for a better pharmacotherapy. Increasing evidence indicate that histone deacetylation is a critical step in nerve injury pain. To obtain an innovative treatment for the management of neuropathic pain, we investigated the pharmacological effects produced by the new histone deacetylase (HDAC)-1 selective inhibitor, LG325, in a mouse model of trauma-induced peripheral mononeuropathy provoked by spared nerve injury (SNI)...
August 15, 2017: Pharmacology, Biochemistry, and Behavior
Chuan-Xi Mao, Xue Wen, Shan Jin, Yong Q Zhang
Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we show that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression...
August 17, 2017: Disease Models & Mechanisms
Rui Xie, Yan Li, Pingwah Tang, Qipeng Yuan
Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
Dongjie Zhou, Yun-Jung Choi, Jin-Hoi Kim
Tubastatin A (Tub-A), a highly selective histone deacetylase 6 (HDAC6) inhibitor, has been widely used as a cytotoxic anticancer agent, or for the treatment of patients with asthma. However, the potential toxicity of Tub-A on oocyte maturation and asymmetric division is still unclear. Therefore, the present study was designed to examine the effect and potential regulatory role of Tub-A on the meiotic maturation of oocytes. We observed that Tub-A treatment induced an increased level of the acetylation of α-tubulin, and a failure of spindle migration and actin cap formation...
August 15, 2017: Scientific Reports
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