• 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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• 제48권3호
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• pp.131-138
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• 2015

Cardiac hypertrophy is a form of global remodeling, although the initial step seems to be an adaptation to increased hemodynamic demands. The characteristics of cardiac hypertrophy include the functional reactivation of the arrested fetal gene program, where histone deacetylases (HDACs) are closely linked in the development of the process. To date, mammalian HDACs are divided into four classes: I, II, III, and IV. By structural similarities, class II HDACs are then subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular function and regulation of class IIa HDACs depend largely on the phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take place primarily in the nucleus. In response to stresses, posttranslational modification (PTM) processes, dynamic modifications after the translation of proteins, are involved in the regulation of the activities of those hypertrophy-related HDACs. In this article, we briefly review 1) the activation of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and its implications in the regulation of HDAC2 activity.

• 생명과학회지
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• 제15권5호
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• pp.726-733
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• 2005

Histone deacetylase (HDAC) 억제제가 새로운 항암치료제 후보물질로서 유용성이 높은 것으로 평가되지만, 아직까지 인체폐암세포에 관한 연구는 상대적으로 미미한 실정이다. 따라서 본 연구에서는 폐암세포에 미치는 HDAC 억제제의 항암작용 기전을 조사하기 위하여 A549 인체폐암세포주를 대상으로 암세포의 증식에 미치는 대표적인 HDAC 억제제인 tichostatin A (TSA)에 의한 영향을 세포주기 조절관련인자 중심으로 조사하였다. TSA의 처리에 의하여 A549 폐암세포의 증식은 처리 농도 의존적으로 억제되었으며, 심한 형태적 변형을 동반하였다. 저농도 처리군에서는 TSA 농도가 증가할수록 세포주기 G1기의 빈도가 증가하였으나, 고농도 처리군에서는 G2/M기에 속하는 세포의 빈도가 증가되었다. 또한 apoptosis 유발의 간접적인 지표가 되는 sub-G1기에 속하는 세포의 빈도 역시 TSA 처리 농도 의존적으로 매우 증가되었다. 이러한 TSA의 A549 폐암세포 증식억제 효과는 cyclins 및 CdkS의 발현 억제, 종양억제유전자인 p53 및 Cdks 억제제인 p21과 p27의 발현 증가와도 연관성이 있었다. TSA의 항암 기전을 규명하기 위해서는 더 많은 연구가 부가적으로 필요하겠지만, 본 연구의 결과들에 의하면 TSA는 강력한 인체폐암세포의 증식 억제 및 항암작용이 있음을 시사하여 준다고 할 수 있다.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.99.2-99.2
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• 2003

One of the major limitations in using adenoviral vector for gene therapy is inefficient infection of host cells. The presence of coxsackievirus and adenovirus receptor (CAR) and ${\alpha}$-integrin on cell surfaces is required for efficient adenovirus infection. In this study, we investigated the effect of trichostatin A, a histone deacetylase inhibitor, on transfection efficiency after transduction of adenovirus mediated p16$\^$INK4a/ gene transfer. In our previous study, p16$\^$INK4a/ tumor suppressor gene transfer in the non-small cell lung cancer cells (A549 cells) by transduction of recombinant adenovirus (Ad5CMV-p16) resulted in significant inhibition of cancer cell proliferation. (omitted)

• 생명과학회지
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• 제26권4호
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• pp.431-438
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• 2016

TRAIL은 정상세포에서는 세포독성을 나타내지 않는 반면, 암세포에서는 사멸을 유도하므로 항암제로 각광받고 있지만 많은 암세포에서 TRAIL에 저항성을 가지고 있는 것으로 알려져 있으므로 이를 극복해야하는 큰 어려움이 남아있다. 본 연구에서는 TRAIL에 저항성을 가지는 인간 방광암 세포주인 5637 세포를 이용하여 histone deacetylase 억제제인 sodium butyrate (SB)와 TRAIL을 혼합처리하였을 경우 유발되는 세포사멸 효과와 이와 관련된 분자생물학적 메카니즘을 연구하였다. 세포독성이 없는 조건의 TRAIL과 SB를 혼합처리 하였을 경우 SB 단독처리군 보다 세포사멸이 현저하게 증가하는 것으로 확인되었다. TRAIL과 SB의 혼합처리는 caspases (caspase-3, -8 and -9)의 활성화 및 PARP의 단편화를 유발하였다. 하지만 caspase 억제제에 의하여 TRAIL과 SB의 혼합처리에 의하여 유발되는 apoptosis가 현저하게 억제되는 것으로 나타났다. 또한 TRAIL과 SB의 혼합처리는 세포표면에 존재하는 DR5의 발현 증가 및 c-FLIP의 발현 감소를 유발하였으며, pro-apoptotic protein인 Bax와 세포질 cytochrome c의 발현 증가 및 anti- apoptotic protein인 Bcl-xL의 발현감소와 함께 tBid의 형성을 유발하였다. 이는 SB와 TRAIL의 혼합처리가 안전하고 선택적으로 TRAIL에 저항성을 가지는 방광암 세포에서 치료하는데 효과적인 전략임을 제시하는 결과이다.

• Molecules and Cells
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• 제40권7호
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• pp.485-494
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• 2017

Oleanolic acid (OA) has neurotrophic effects on neurons, although its use as a neurological drug requires further research. In the present study, we investigated the effects of OA and OA derivatives on the neuronal differentiation of rat hippocampal neural progenitor cells. In addition, we investigated whether the class II histone deacetylase (HDAC) 5 mediates the gene expression induced by OA. We found that OA and OA derivatives induced the formation of neurite spines and the expression of synapse-related molecules. OA and OA derivatives stimulated HDAC5 phosphorylation, and concurrently the nuclear export of HDCA5 and the expression of HDAC5 target genes, indicating that OA and OA derivatives induce neural differentiation and synapse formation via a pathway that involves HDAC5 phosphorylation.

• Asian-Australasian Journal of Animal Sciences
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• 제30권6호
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• pp.857-864
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• 2017

Objective: The purpose of this study was to investigate the influence of AMP-activated protein kinase (AMPK) activation on protein acetylation and glycolysis in postmortem muscle to better understand the mechanism by which AMPK regulates postmortem glycolysis and meat quality. Methods: A total of 32 mice were randomly assigned to four groups and intraperitoneally injected with 5-Aminoimidazole-4-carboxamide1-${\beta}$-D-ribofuranoside (AICAR, a specific activator of AMPK), AICAR and histone acetyltransferase inhibitor II, or AICAR, Trichostatin A (TSA, an inhibitor of histone deacetylase I and II) and Nicotinamide (NAM, an inhibitor of the Sirt family deacetylases). After mice were euthanized, the Longissimus dorsi muscle was collected at 0 h, 45 min, and 24 h postmortem. AMPK activity, protein acetylation and glycolysis in postmortem muscle were measured. Results: Activation of AMPK by AICAR significantly increased glycolysis in postmortem muscle. At the same time, it increased the total acetylated proteins in muscle 45 min postmortem. Inhibition of protein acetylation by histone acetyltransferase inhibitors reduced AMPK activation induced increase in the total acetylated proteins and glycolytic rate in muscle early postmortem, while histone deacetylase inhibitors further promoted protein acetylation and glycolysis. Several bands of proteins were detected to be differentially acetylated in muscle with different glycolytic rates. Conclusion: Protein acetylation plays an important regulatory role in postmortem glycolysis. As AMPK mediates the effects of pre-slaughter stress on postmortem glycolysis, protein acetylation is likely a mechanism by which antemortem stress influenced postmortem metabolism and meat quality though the exact mechanism is to be elucidated.

• Reproductive and Developmental Biology
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• 제35권2호
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• pp.159-165
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• 2011

To explore the role of histone deactylase (HDAC) activation in an in vivo model of hypertrophy, we studied the effects of Trichostatin A (TSA). TSA subjected to thoracic aortic banding (TAB)-induced pressure stress in mice. In histological observations, TAB in treated mice showed a significant hypertrophic response, whereas the sham operation remained nearly normal structure with partially blunted hypertrophy. TSA treatment had no effect (measured as HW/BW) on sham-operated animals. TAB animals treated with vehicle manifested a robust ~50% hypertrophic response (p<0.05 vs sham). TAB mice treated with 2 mg/kg/day TSA manifested a blunted growth responses, which was significantly diminished (p<0.05) compared with vehicle-treated TAB mice. TAB mice treated with a lower dose of TSA (0.5 mg/kg/day) manifested a similar blunting of hypertrophic growth (~25% increase in heart mass). Furthermore, to determine activity duration of TSA in vitro, 1 nM TSA was added to H9c2 cells. Histone acetylation was initiated at 4 hr after treatment, and it was peak up to 18 hr, then followed by significantly reduced to 30 hr. We also analyzed the expression of p53 following TSA treatment, wherein p53 expression was elevated at 4 hr, and it was maintained to 24 hr after treatment. ERK was activated at 8 hr, and maintained till 30 hr after treatment suggesting an intracellular signaling interaction between TSA and p53 expression Taken together, it is suggested that HDAC activation is required for pressure-overload growth of the heart. Eventually, these data suggest that histone acetylation may be a novel target for therapeutic intervention in pressure-overloaded cardiac hypertrophy.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7095-7100
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• 2013

Histone deacetylase (HDAC) inhibitors of cyclic peptide have been proved to be the most complex but the most stable and relative efficient inhibitors because of their large cap region. In this paper, a series of studies were carried out to evaluate the efficacy of synthetic bicyclic tetrapeptide inhibitors 1-5 containing hydroxamic acid referring molecular docking, anti-proliferation, morphology and apoptosis. Docking analysis, together with enzyme inhibitory results, verified the selective capability of inhibitor 4 to HDAC4, which might closely related to haematological tumorigenesis, with Phe227, Asp115, Pro32, His198 and Ser114 participating into hydrophobic interactions and Van der Waals force which was familiar with former study. Moreover, inhibitor 4 inhibited K562 cell line at the $IC_{50}$ value of 1.22 ${\mu}M$ which was 51-67 times more efficient than that for U937 and HL60 cell lines. Inhibitor 4 exhibited the cell cycle-arrested capability to leukemia at S phase or G2/M phase as well as apoptosis-induced ability in different degrees. Finally, we considered that bicyclic tetrapeptide inhibitors were promising inhibitors used in cancer treatment and inhibitor 4 could prevent K562 cell line well from proliferation, arrest cell cycle and induce K562 towards apoptosis to achieve the goals of reversing cancer cells which could become a potential leukemia therapeutic agent in the future.

• 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.