• 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.

• Molecules and Cells
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• 제43권10호
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• pp.841-847
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• 2020

Histone acetylation and deacetylation play central roles in the regulation of chromatin structure and transcription by RNA polymerase II (RNA Pol II). Although Hda1 histone deacetylase complex (Hda1C) is known to selectively deacetylate histone H3 and H2B to repress transcription, previous studies have suggested its potential roles in histone H4 deacetylation. Recently, we have shown that Hda1C has two distinct functions in histone deacetylation and transcription. Histone H4-specific deacetylation at highly transcribed genes negatively regulates RNA Pol II elongation and H3 deacetylation at inactive genes fine-tunes the kinetics of gene induction upon environmental changes. Here, we review the recent understandings of transcriptional regulation via histone deacetylation by Hda1C. In addition, we discuss the potential mechanisms for histone substrate switching by Hda1C, depending on transcriptional frequency and activity.

• 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.

• 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.

• 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.

• BMB Reports
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• 제47권4호
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• pp.227-232
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• 2014

Histone deacetylase-3 (HDAC3) is involved in cellular proliferation, apoptosis and transcriptional repression. However, the role of HDAC3 in angiogenesis remains unknown. HDAC3 negatively regulated the expression of angiogenic factors, such as VEGF and plasminogen activator inhibitor-1 (PAI-1). HDAC3 showed binding to promoter sequences of PAI-1. HDAC3 activity was necessary for the expression regulation of PAI-1 by HDAC3. VEGF decreased the expression of HDAC3, and the down-regulation of HDAC3 enhanced endothelial cell tube formation. HDAC3 negatively regulated tumor-induced angiogenic potential. We show the novel role of HDAC3 as a negative regulator of angiogenesis.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2003년도 Annual Meeting of KSAP : International Symposium on Pharmaceutical and Biomedical Sciences on Obesity
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• pp.88-88
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• 2003

Cytochrome P-450 3A4 (CYP3A4) is major enzyme in human liver, the role of this is detoxification and metabolizing more than 50% clinical drugs in use. Expression of CYP3A4 is transciptionally regulated by the Pregnenolone X receptor (PXR), of which human form is Steroid and Xenobiotics receptor (SXR). SXR is activated by wide range of endogenous and exogenous compounds, and then induces CYP3A4 gene expression. In the previous study, it has been known that proximal promoter (-864 to +64) does not response to chemical inducers such as pregnenolone 16a-carbonitrile (PCN), Rifampicin, Estrogen in terms of transcription of CYP 3A4 in cultured cells. Here, we developed luciferase reporter gene assay system to detect SXR-based CYP 3A4 transcriptional activity. We have used CYP3A4-Luc plasmid that contains proximal promoter of human CYP3A4 gene upstream of the luciferase gene. We did transient transfection of 3A4-luciferase gene and SXR. In the HepG2 cells transfected with CYP3A4-Luc, when rifampicin treatment was combined with histone deacetylase inhibitor (HDAC Inhibitor), such as Trichostatin A, Hc-toxin and IN 2001 of the luciferase activity was induced 10-20 fold over control.

• 한국환경독성학회:학술대회논문집
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• 한국환경독성학회 2003년도 추계국제학술대회
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• pp.178-178
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• 2003

Cytochrome P-450 3A4 (CYP3A4) is major enzyme in human liver, the role of this Is detoxification and metabolizing more than 50% clinical drugs in use. Expression of CYP3A4 is transciptionally regulated by the Pregnenolone X receptor (PXR), of which human form is Steroid and Xenobiotics receptor (SXR). SXR is activated by wide range of endogenous and exogenous compounds, and then induces CYP3A4 gene expression. In the previous study, it has been known that proximal promoter (-864 to ＋64) does not response to chemical inducers such as pregnenolone 16a-carbonitrile (PCN), Rifampicin, Estrogen in terms of transcription of CYP 3A4 in cultured cells. Here, we developed luciferase reporter gene assay system to detect SXR-based CYP 3A4 transcriptional activity. We have used CYP3A4-Luc plasmid that contains proximal promoter of human CYP3A4 gene upstream of the luciferase gene. We did transient transfection of 3A4-luciferase gene and SXR. In the HepG2 cells transfected with CYP3A4-Luc, when rifampicin treatment was combined with histone deacetylase inhibitor (HDAC Inhibitor), such as Trichostatin A, Hc-toxin and IN 2001 of the luciferase activity was induced 10-20 fold over control.

• 대한약침학회지
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• 제16권4호
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• pp.7-13
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• 2013

Objectives: Whether the ultra-highly-diluted remedies used in homeopathy can effectively bring about modulations of gene expressions through acetylation/deacetylation of histones has not been explored. Therefore, in this study, we pointedly checked if the homeopathically-diluted anti-cancer remedy Condurango 30C (ethanolic extract of Gonolobus condurango diluted $10^{-60}$ times) was capable of arresting the cell cycles in cervical cancer cells HeLa by triggering an epigenetic modification through modulation of the activity of the key enzyme histone deacetylase 2 vis-a-vis the succussed alcohol (placebo) control. Methods: We checked the activity of different signal proteins (like $p21^{WAF}$, p53, Akt, STAT3) related to deacetylation, cell growth and differentiation by western blotting and analyzed cell-cycle arrest, if any, by fluorescence activated cell sorting. After viability assays had been performed with Condurango 30C and with a placebo, the activities of histone de-acetylase (HDAC) enzymes 1 and 2 were measured colorimetrically. Results: While Condurango 30C induced cytotoxicity in HeLa cells in vitro and reduced HDAC2 activity quite strikingly, it apparently did not alter the HDAC1 enzyme; the placebo had no or negligible cytotoxicity against HeLa cells and could not alter either the HDAC 1 or 2 activity. Data on $p21^{WAF}$, p53, Akt, and STAT3 activities and a cell-cycle analysis revealed a reduction in DNA synthesis and G1-phase cell-cycle arrest when Condurango 30C was used at a 2% dose. Conclusion: Condurango 30C appeared to trigger key epigenetic events of gene modulation in effectively combating cancer cells, which the placebo was unable to do.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2005년도 춘계 국제심포지엄 및 학술대회
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• pp.180-180
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• 2005