• Molecules and Cells
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• 제22권2호
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• pp.163-167
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• 2006

Histone deacetylase (HDAC) activity is commonly associated with transcriptional repression. However, there is also evidence for a function in transcriptional activation. Previous studies have demonstrated a fundamental role of deacetylase activity in $IFN{\alpha}$-responsive gene transcription. In the case of type II IFN ($IFN{\gamma}$) results are controversial: some genes require HDAC activity, while transcription of others is repressed by HDAC. To investigate the effect of HDAC on transcription of an $IFN{\gamma}$-activated gene, real-time PCR was used to measure CXCL10 mRNA in Hela cells stimulated with $IFN{\gamma}$ in the presence or absence of the HDAC inhibitor TSA. Chromatin imunoprecipitation combined with real-time PCR was used to check acetylation of histone H4 and recruitment of the STAT1 complex to the ISRE locus of the CXCL10 gene. Activation of CXCL10 transcription in response to $IFN{\gamma}$ was paralleled by a decrease in histone H4 acetylation and an increase in recruitment of the STAT1 complex to the CXCL10 ISRE locus. The transcription of CXCL10 and histone H4 deacetylation were blocked by TSA, but the latter had no obvious affect on recruitment of the STAT1 complex. Our data indicate that $IFN{\gamma}$ and STAT-dependent gene transcription requires the participation of HDAC, as does the $IFN{\alpha}$-STAT pathway.

• Environmental Analysis Health and Toxicology
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• 제27권
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• pp.10.1-10.7
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• 2012

Objectives: In recent years, a number of structurally diverse Histone deacetylase (HDAC) inhibitors have been identified and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. This study aimed at investigating the antitumor activity of newly synthesized HDAC inhibitor, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide (IN-2001) using human breast cancer cells. Methods: We have synthesized a new HDAC inhibitor, IN-2001, and cell proliferation inhibition assay with this chemical in estrogen receptor-positive human breast cancer MCF-7 cells. Cell cycle analysis on MCF-7 cells treated with IN-2001 was carried out by flow cytometry and gene expression was measured by RT-PCR. Results: In MCF-7 cells IN-2001 showed remarkable anti-proliferative effects in a dose- and time-dependent manner. In MCF-7 cells, IN-2001 showed a more potent growth inhibitory effect than that of suberoylanilide hydroxamic acid. These growth inhibitory effects were related to the cell cycle arrest and induction of apoptosis. IN-2001 showed accumulation of cells at $G_2$/M phase and of the sub-$G_1$ population in a time-dependent manner, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with HDAC inhibitor-mediated induction of CDK inhibitor expression. In MCF-7 cells, IN-2001 significantly increased $p21^{WAF1}$ expression. Conclusions: In summary, cyclin-dependent kinase (CDK) induced growth inhibition, possibly through modulation of cell cycle and apoptosis regulatory proteins, such as CDK inhibitors, and cyclins. Taken together, these results provide an insight into the utility of HDAC inhibitors as a novel chemotherapeutic regime for hormone-sensitive and insensitive breast cancer.

• Interdisciplinary Bio Central
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• 제4권1호
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• pp.2.1-2.7
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• 2012

Introduction: Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from ${\varepsilon}$-N-acetyl lysine amino acids of histone proteins. Their action is opposite to that of histone acetyltransferase that adds acetyl groups to these lysines. Only few HDAC inhibitors are approved and used as anti-cancer therapeutics. Thus, discovery of new and potential HDAC inhibitors are necessary in the effective treatment of cancer. Materials and Methods: This study proposed a method using support vector machine (SVM) to classify HDAC8 inhibitors and non-inhibitors in early-phase virtual compound filtering and screening. The 100 experimentally known HDAC8 inhibitors including 52 inhibitors and 48 non-inhibitors were used in this study. A set of molecular descriptors was calculated for all compounds in the dataset using ADRIANA. Code of Molecular Networks. Different kernel functions available from SVM Tools of free support vector machine software and training and test sets of varying size were used in model generation and validation. Results and Conclusion: The best model obtained using kernel functions has shown 75% of accuracy on test set prediction. The other models have also displayed good prediction over the test set compounds. The results of this study can be used as simple and effective filters in the drug discovery process.

• Bulletin of the Korean Chemical Society
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• 제32권6호
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• pp.1891-1896
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• 2011

On the basis of potent HDAC-inhibitory activity and anticancer activity of SAHA, novel SAHA derivatives 3a-d and 7 with a bulky cap such as p-dimethylaminophenyl, 4-phenylaminophenyl, 4-phenyloxyphenyl, 9H-fluorenyl or naphthalenyl ring were synthesized starting from the corresponding aryl amines or naphthalenyl acetic acid using an EDC-mediated amide coupling reaction in the presence of HOBt followed by a nucleophilic addition-elimination reaction with hydroxylamine. Compounds 3b, 3c and 3d showed more potent inhibitory activity on total HDACs (14~27-fold), HDAC1 (8~15-fold), HDAC2 (1.3~25-fold) and HDAC7 (1~3-fold) and more potent anticancer activity (2~22-fold) against MCF-7, MDA-MB-231, MCF-7/Dox, MCF-7/Tam, SK-OV-3, LNCaP and PC3 human cancer cell lines than SAHA.

• 통합자연과학논문집
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• 제12권4호
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• pp.133-141
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• 2019

Mesenchymal stem cells (MSCs) are known to differentiate into multiple lineages, making neurogenic differentiation an important target in the clinical field. In the present study, we induced the neurogenic differentiation of cells using histone deacetylase (HDAC) inhibitors and studied their mechanisms for further differentiation in vitro. We treated cells with the HDAC inhibitors, MS-275 and NaB; and found that the cells had neuron-like features such as distinct bipolar or multipolar morphologies with branched processes. The mRNA expressions encoding for NEFL, MAP2, TUJ1, OLIG2, and SYT was significantly increased following HDAC inhibitors treatment compared to without HDAC inhibitors; high protein levels of MAP2 and Tuj1 were detected by immunofluorescence staining. We examined the mechanisms of differentiation and found that the Wnt signaling pathway and downstream mitogen-activate protein kinase were involved in neurogenic differentiation of MSCs. Importantly, Wnt4, Wnt5a/b, and Wnt11 protein levels were highly increased after treatment with NaB; signals were activated through the regulation of Dvl2 and Dvl3. Interestingly, NaB treatment increased the levels of JNK and upregulated JNK phosphorylation. After MS-275 treatment, Wnt protein levels were decreased and GSK-3β was phosphorylated. In this cell, HDAC inhibitors controlled the non-canonical Wnt expression by activating JNK phosphorylation and the canonical Wnt signaling by targeting GSK-3β.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.155-162
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• 2018

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP.

• BMB Reports
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• 제50권4호
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• pp.162-163
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• 2017

RNA polymerase II-interacting the Set2 methyltransferase co-transcriptionally methylates histone H3 at lysine 36 within the body of genes. This modification facilitates histone deacetylation by Rpd3S HDAC in 3' transcribed regions to suppress cryptic initiation and slow elongation. Although this pathway is important for global deacetylation, no strong effects have been seen on genome-wide transcription under optimized laboratory conditions. In contrast, this pathway slows the kinetics of mRNA induction when target genes are induced upon environmental changes. Interestingly, a majority of Set2-repressed genes are overlapped by a lncRNA transcription that targets H3K36 methylation and deacetylation by Rpd3S HDAC to mRNA promoters. Furthermore, this pathway delays the induction of many cryptic transcripts upon environmental changes. Therefore, the Set2-Rpd3S HDAC pathway functions to fine-tune expression dynamics of mRNAs and ncRNAs.

• Journal of Microbiology and Biotechnology
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• 제26권4호
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• pp.693-699
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• 2016

Clostridium difficile toxin A is known to cause deacetylation of tubulin proteins, which blocks microtubule formation and triggers barrier dysfunction in the gut. Based on our previous finding that the Clostridium difficile toxin A-dependent activation of histone deacetylase 6 (HDAC-6) is responsible for tubulin deacetylation and subsequent microtubule disassembly, we herein examined the possible effect of potassium acetate (PA; whose acetyl group prevents the binding of tubulin to HDAC-6) as a competitive/false substrate. Our results revealed that PA inhibited toxin A-induced deacetylation of tubulin and recovered toxin A-induced microtubule disassembly. In addition, PA treatment significantly decreased the production of IL-6 (a marker of inflamed tissue) in the toxin A-induced mouse enteritis model. An in vitro HDAC assay revealed that PA directly inhibited HDAC-6-mediated tubulin deacetylation, indicating that PA acted as a false substrate for HDAC-6. These results collectively indicate that PA treatment inhibits HDAC-6, thereby reducing the cytotoxicity and inflammatory responses caused by C. difficile toxin A.

• 한국발생생물학회지:발생과생식
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• 제17권4호
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• pp.379-387
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• 2013

Embryonic stem (ES) cells can self-renew and differentiate to various cells depending on the culture condition. Although ES cells are a good model for cell type specification and can be useful for application in clinics in the future, studies on ES cells have many experimental restraints including low transfection efficiency and transgene expression. Here, we observed that transgene expression after transfection was enhanced by treatment with histone deacetylse (HDAC) inhibitors such as trichostatin A, sodium butyrate, and valproic acid. Transfection was performed using conventional transfection reagents with a retroviral vector encoding GFP under the control of CMV promoter as a reporter. Treatment of ES cells with HDAC inhibitors after transfection increased population of GFP positive cells up to 180% compared with untreated control. ES cells showed normal expression of stem cell markers after treatment with HDAC inhibitors. Transgene expression was further enhanced by modifying transfection procedure. GFP positive cells selected after transfection were proved to have the stem cell properties. Our improved protocol for enhanced gene delivery and expression in mouse ES cells without hampering ES cell properties will be useful for study and application of ES cells.

• 생명과학회지
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• 제17권4호
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• pp.552-560
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• 2007

본 연구에서는 인체백혈병세포 U937에서 HDAC 저해제에 의한 증식억제, 세포주기 교란 및 apoptosis 유도에 미치는 Bcl-2 유전자의 영향에 관하여 조사하였다. 이를 위하여 U937/vector 및 U937/Bcl-2 세포주를 대상으로 대표적인 HDAC 저해제인 TSA 및 Na-B 처리에 의한 세포 증식 및 생존율에 미치는 영향을 조사한 결과, TSA에 의한 U937 세포의 증식억제 및 생존율의 감소는 Bcl-2의 과발현에 의하여 차단되는 효과를 보였으나, Na-B는 U937/vector 및 U937/Bcl-2세포사이에 큰 변화를 보이지는 않았다. 세포주기 교란효과에서 Na-B는 TSA에 비하여 유의적인 차이를 보이지 못하였으며, 이는 TSA에 의한 apoptosis가 U937/Bcl-2 세포에서는 억제되었으나, Na-B에 의한 apoptosis는 Bcl-2의 과발현에 의하여 차단되지 못한 것과 연관성이 있는 결과였다. 또한 TSA에 의한 apoptosis 유발의 Bcl-2에 의한 차단 효과는 TSA에 의하여 활성화된 caspase의 활성 억제, Bcl-2 발현 자체의 완화 등 apoptosis 조절 인자들의 발현 및 활성 변화에 기인 된 것임을 알 수 있었다.