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Benjamin Y Owusu, Lidija Klampfer
The luciferase (LUC) reporter assay is commonly used to study gene expression at the transcriptional level. It is convenient, fast, sensitive, inexpensive, and provides quantitative data about small changes in transcription. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that plays a crucial role in signaling by interferons (IFNs). Here, we describe LUC reporter studies that address the role of histone deacetylase (HDAC) activity in STAT1-dependent gene activation. These experiments include overexpression of HDAC1, HDAC2, HDAC3, and HDAC4 as well as silencing of HDAC1, HDAC2, and HDAC3 through RNA interference in mammalian cancer cells...
2017: Methods in Molecular Biology
Juanmei Gao, Hangze Ruan, Xianjie Qi, Yi Tao, Xia Guo, Wanhua Shen
Radial glial cells (RGs) are one of the important progenitor cells that can differentiate into neurons or glia to form functional neural circuits in the developing central nervous system (CNS). Histone deacetylases (HDACs) has been associated with visual activity dependent changes in BrdU-positive progenitor cells in the developing brain. We previously have shown that HDAC1 is involved in the experience-dependent proliferation of RGs. However, it is less clear whether two other members of class I HDACs, HDAC2 and HDAC3, are involved in the regulation of radial glia proliferation...
2016: Frontiers in Cellular Neuroscience
N Stojanovic, Z Hassan, M Wirth, P Wenzel, M Beyer, C Schäfer, P Brand, A Kroemer, R H Stauber, R M Schmid, A Arlt, A Sellmer, S Mahboobi, R Rad, M Reichert, D Saur, O H Krämer, G Schneider
Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels...
October 10, 2016: Oncogene
Chengdu Sun, Liming Wang, Dan Gao, Yuanming Pan, Yuliang Zhao, Chunying Chen, Mingzhou Guo
C60(OH)22 has been reported to suppress human cancer by inhibiting angiogenesis. However, its mechanism of action remains unclear. To explore the role and mechanism of C60(OH)22 in human pancreatic cancer, siRNA knockdown, immunofluorescence and a matrigel plug mouse model were employed. The results demonstrated that C60(OH)22 suppresses endothelial cell invasion and tube formation in vitro. C60(OH)22 suppresses angiogenesis in human umbilical vein endothelial cell (HUVEC) xenograft mice. The enzymatic activities of MMP2 and MMP9, as well as the expression levels of HDAC1, HDAC2, HIF-1α and VEGF, were inhibited by C60(OH)22...
September 15, 2016: Nanoscale
Keffy Kehrli, Michael Phelps, Pavlo Lazarchuk, Eleanor Chen, Raymond Monnat, Julia M Sidorova
The WRN helicase/exonuclease is mutated in Werner syndrome of genomic instability and premature aging. WRN-depleted fibroblasts, while remaining largely viable, have a reduced capacity to maintain replication forks active during a transient hydroxyurea-induced arrest. A strand exchange protein RAD51 is also required for replication fork maintenance, and here we show that recruitment of RAD51 to stalled forks is reduced in the absence of WRN. We performed a siRNA screen for genes that are required for viability of WRN-depleted cells after hydroxyurea treatment, and identified HDAC1, a member of the class I histone deacetylase family...
September 26, 2016: Journal of Biological Chemistry
Melissa Mahgoub, Megumi Adachi, Kanzo Suzuki, Xihui Liu, Ege T Kavalali, Maria H Chahrour, Lisa M Monteggia
Class I histone deacetylases (HDACs) Hdac1 and Hdac2 can associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined whether Hdac1 and Hdac2 were functionally redundant in mature mouse brain. We demonstrate that postnatal forebrain-specific deletion of both Hdac1 and Hdac2 in mice impacts neuronal survival and results in an excessive grooming phenotype caused by dysregulation of Sap90/Psd95-associated protein 3 (Sapap3; also known as Dlgap3) in striatum...
September 26, 2016: Nature Neuroscience
Alexander Beck, Corinna Eberherr, Michaela Hagemann, Stefano Cairo, Beate Häberle, Christian Vokuhl, Dietrich von Schweinitz, Roland Kappler
Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of 3 y. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option...
September 16, 2016: Cancer Biology & Therapy
Sahil Sharma, Fabian Poetz, Marius Bruer, Thi Bach Nga Ly-Hartig, Johanna Schott, Bertrand Séraphin, Georg Stoecklin
Acetylation of histones and transcription-related factors is known to exert epigenetic and transcriptional control of gene expression. Here we report that histone acetyltransferases (HATs) and histone deacetylases (HDACs) also regulate gene expression at the posttranscriptional level by controlling poly(A) RNA stability. Inhibition of HDAC1 and HDAC2 induces massive and widespread degradation of normally stable poly(A) RNA in mammalian and Drosophila cells. Acetylation-induced RNA decay depends on the HATs p300 and CBP, which acetylate the exoribonuclease CAF1a, a catalytic subunit of the CCR4-CAF1-NOT deadenlyase complex and thereby contribute to accelerating poly(A) RNA degradation...
September 15, 2016: Molecular Cell
Ye Wang, Tao Jin, Xueming Dai, Dongwang Yan, Zhihai Peng
The aim of the present study was to screen the enzymes that are associated with the radiosensitivity of SW579 thyroid cancer cells, and investigate whether radiation, combined with specific RNA interference on the screened enzymes, enhances radiosensitivity of SW579 thyroid cancer cells. Quantitative polymerase chain reaction (qPCR) was used to analyze epigenetic enzyme expression changes before and after radiotherapy, and four enzymes, histone deacetylase 1 (HDAC1), HDAC2, HDAC4 and HDAC6 were screened. Western blot analysis was performed to analyze the change in HDAC1, HDAC2, HDAC4 and HDAC6 protein expression following radiotherapy...
October 2016: Molecular Medicine Reports
Haishan Zhao, Zhaojin Yu, Lin Zhao, Miao He, Jie Ren, Huizhe Wu, Qiuchen Chen, Weifan Yao, Minjie Wei
OBJECTIVE: Previous studies have revealed the association of multidrug resistance with histone deacetylases inhibitors treatment in cancer cells. But little data were available for the correlation of histone deacetylases and drug-resistant-related proteins in breast cancer tissue. This study aimed to exploring the association of histone deacetylases expression with clinicopathological features, drug-resistant-related proteins, prognosis and therapeutic responses in breast cancer patients...
July 18, 2016: Japanese Journal of Clinical Oncology
Tripti Singh, Ram Prasad, Santosh K Katiyar
Lung cancer and its metastasis is the leading cause of cancer-related mortality world-wide. Non-small cell lung cancer (NSCLC) accounts for about 90% of total lung cancer cases. Despite advancements in therapeutic approaches, only limited improvement has been achieved. Therefore, alternative strategies are required for the management of lung cancer. Here we report the chemotherapeutic effect of silymarin, a phytochemical from milk thistle plant (Silybum marianum L. Gaertn.), on NSCLC cell migration using metastatic human NSCLC cell lines (A549, H1299 and H460) together with the molecular targets underlying these effects...
2016: American Journal of Cancer Research
Tianyi Zhang, Zhentao Sheng, Wei Du
Inactivation of HDAC1 and its homolog HDAC2 or addition of HDAC inhibitors in mammalian systems induces apoptosis, cell cycle arrest, and developmental defects. Although these phenotypes have been extensively characterized, the precise underlying mechanisms remain unclear, particularly in in vivo settings. In this study, we show that inactivation of Rpd3, the only HDAC1 and HDAC2 ortholog in Drosophila, induced apoptosis and clone elimination in the developing eye and wing imaginal discs. Depletion of Rpd3 by RNAi cell-autonomously increased JNK activities and decreased activities of Yki, the nuclear effecter of Hippo signaling pathway...
August 2016: Mechanisms of Development
Florence F Wagner, Michel Weïwer, Stefan Steinbacher, Adrian Schomburg, Peter Reinemer, Jennifer P Gale, Arthur J Campbell, Stewart L Fisher, Wen-Ning Zhao, Surya A Reis, Krista M Hennig, Méryl Thomas, Peter Müller, Martin R Jefson, Daniel M Fass, Stephen J Haggarty, Yan-Ling Zhang, Edward B Holson
The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2...
September 15, 2016: Bioorganic & Medicinal Chemistry
Thanaphum Osathanon, Nunthawan Nowwarote, Prasit Pavasant
Notch signaling dysregulation plays an important role in altering cancer cell behaviors; however, its role in oral squamous cell carcinoma (OSCC) remains controversial. This study aimed to investigate the role of Notch signaling related genes in human OSCC using a meta-analysis of Gene Expression Omnibus database (GEO-publicly available gene expression microarray data) and to examine the role of Notch signaling in OSCC behaviors. The meta-analysis included 13 GEO datasets and was performed by combining effect sizes in a random effect model...
2016: Journal of Oral Science
Yidi Guo, Xueqi Fu, Bo Huo, Yongsen Wang, Jing Sun, Lingyuan Meng, Tian Hao, Zhizhuang Joe Zhao, Xin Hu
The dynamic and reversed expression of GATA1 and GATA2 are essential for proper erythroid differentiation. Our previous work demonstrates that LSD1, a histone H3K4 demethylase, represses GATA2 expression at late stage of erythroid differentiation. K562 and MEL cells were used and cultured in Roswell Park Memorial Institute-1640 medium (RPMI) and Dulbecco's modified Eagle's medium (DMEM), respectively. Western blot assay was used to examine the GATA1, GATA2, TAL1, HDAC1, HDAC2, CoREST and β-actin protein. The immunoprecipitation assay and GST pull-down assay were employed to detect the precipitated protein complexes and investigate the interaction between the proteins...
2016: American Journal of Translational Research
Reena Buurman, Maria Sandbothe, Brigitte Schlegelberger, Britta Skawran
BACKGROUND: Histone deacetylation, a common hallmark in malignant tumors, strongly alters the transcription of genes involved in the control of proliferation, cell survival, differentiation and genetic stability. We have previously shown that HDAC1, HDAC2, and HDAC3 (HDAC1-3) genes encoding histone deacetylases 1-3 are upregulated in primary human hepatocellular carcinoma (HCC). The aim of this study was to characterize the functional effects of HDAC1-3 downregulation and to identify functionally important target genes of histone deacetylation in HCC...
2016: European Journal of Medical Research
Alex Sotolongo, Fabiola Zakia Mónica, Alex Kots, Haijie Xiao, Jun Liu, Edward Seto, Ka Bian, Ferid Murad
Soluble guanylate cyclase (sGC) is a heterodimer composed of α and β subunits. The loss of sGCβ1 has been implicated in several vascular and nonvascular diseases. Our analysis showed that higher levels of sGCβ1 in breast cancer tissues are correlated with greater survival probability than lower sGCβ1 levels. However, there is no information on sGC regulation by epigenetic mechanisms. We examined the role of histone deacetylase (HDAC) inhibitors in regulating sGCα1 and -β1 expression in human breast cancer MDA-MB-231 and MDA-MB-468 cell lines...
September 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Naveen K Somanna, Anthony J Valente, Maike Krenz, Kerry S McDonald, Yusuke Higashi, Makoto Noda, Bysani Chandrasekar
Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction...
June 9, 2016: Hypertension Research: Official Journal of the Japanese Society of Hypertension
Hyuck Kim, Christina N Ramirez, Zheng-Yuan Su, Ah-Ng Tony Kong
Ursolic acid (UA), a well-known natural triterpenoid found in abundance in blueberries, cranberries and apple peels, has been reported to possess many beneficial health effects. These effects include anticancer activity in various cancers, such as skin cancer. Skin cancer is the most common cancer in the world. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of antioxidative stress response with anticarcinogenic activity against UV- and chemical-induced tumor formation in the skin. Recent studies show that epigenetic modifications of Nrf2 play an important role in cancer prevention...
July 2016: Journal of Nutritional Biochemistry
Maria Pinkerneil, Michèle J Hoffmann, Hella Kohlhof, Wolfgang A Schulz, Günter Niegisch
BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models...
June 2, 2016: Targeted Oncology
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