• IMMUNE NETWORK
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• v.13 no.2
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• pp.75-79
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• 2013

Evidence for immunoregulatory roles of prostaglandins (PGs) is accumulating. Since our observation of PG production by human follicular dendritic cells (FDCs), we investigated the regulatory mechanism of PG production in FDC and attempted to understand the functions of released PGs in the responses of adjacent lymphocytes. Here, using FDC-like cells, HK cells, we analyzed protein expression alterations in cyclooxygenase-2 (COX-2) in the presence of IL-4 or histone deacetylase (HDAC) inhibitors. Both IL-4 and HDAC inhibitors suppressed COX-2 expression in dose-dependent manners. Their effect was specific to COX-2 and did not reach to COX-1 expression. Interestingly, HDAC inhibitors gave rise to an opposing effect on COX-2 expression in peripheral blood monocytes. Our results suggest that IL-4 may regulate COX-2 expression in FDCs by affecting chromatin remodeling and provide insight into the role of cellular interactions between T cells and FDC during the GC reaction. Given the growing interests in wide-spectrum HDAC inhibitors, the differential results on COX-2 expression in HK cells and monocytes raise cautions on their clinical use.

• BMB Reports
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• v.56 no.7
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• pp.398-403
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• 2023

Natural killer (NK) cells are an essential part of the innate immune system that helps control infections and tumors. Recent studies have shown that Vorinostat, a histone deacetylase (HDAC) inhibitor, can cause significant changes in gene expression and signaling pathways in NK cells. Since gene expression in eukaryotic cells is closely linked to the complex three-dimensional (3D) chromatin architecture, an integrative analysis of the transcriptome, histone profiling, chromatin accessibility, and 3D genome organization is needed to gain a more comprehensive understanding of how Vorinostat impacts transcription regulation of NK cells from a chromatin-based perspective. The results demonstrate that Vorinostat treatment reprograms the enhancer landscapes of the human NK-92 NK cell line while overall 3D genome organization remains largely stable. Moreover, we identified that the Vorinostat-induced RUNX3 acetylation is linked to the increased enhancer activity, leading to elevated expression of immune response-related genes via long-range enhancer-promoter chromatin interactions. In summary, these findings have important implications in the development of new therapies for cancer and immune-related diseases by shedding light on the mechanisms underlying Vorinostat's impact on transcriptional regulation in NK cells within the context of 3D enhancer network.

• Radiation Oncology Journal
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• v.22 no.2
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• pp.138-141
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• 2004

Purpose : We have previously reported that human glioblastoma cells are sensitized to radiation-induced death after their exposure to trichostatin A (TSA), a histone deacetylase inhibitor (HDAC-1), prior to the irradiation. We aimed to measure the magnitude of the radiosensitizing effect of TSA in human head and neck cancer cell lines. Materials and Methods : Human head and neck cancer cell lines, HN-3 and HN-9, were exposed to 0, 50, 100, and 200 nM TSA for 18 hr prior to irradiation. Then, the TSA-treated cells were irradiated with 0, 2, 4, 6, and 8 Gy, and cell survival was measured by clonogenic assay. Results : Pre-irradiation exposure to TSA was found to radiosensitize HN-3 and HN-9 cell lines. In HN-9 cells, the fraction surviving after 2 Gy (SF2) was significantly reduced by treatment of TSA at concentration as low as 50 nM. However, a treatment with 200 nM TSA was required to significantly decrease SF2 in the HN-3 cell line. SER of pre-irradiation treatment with 200 nM TSA was 1.84 in HN-3 and 7.24 in HN-9, respectively. Conclusions : Our results clearly showed that human head and neck cancer cell lines can be sensitized to ionizing radiation by pre-irradiation inhibition of histone deacetylase (HDAC) using TSA, and that this potentiation might well be a general phenomenon.

• Archives of Pharmacal Research
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• v.27 no.4
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• pp.415-421
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• 2004

Cytochrome P450 3A4 (CYP3A4) is the most abundant CYPs in human liver, comprising approximately $30\%$ of the total liver CYPs contents and is involved in the metabolism of more than $60\%$ of currently used therapeutic drugs. However, the molecular mechanisms underly-ing regulation of CYP3A4 gene expression have not been understood. Thus, this study has been carried out to gain the insight of the molecular mechanism of CYP3A4 gene expression, investigating if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter. Also SXR was investigated to see if they were involved in the regulation of CYP3A4 proximal promoter activity. Hepa-1 cells were transfected with a plasmid containing ${\~}1kb$ of the human CYP3A4 proximal promoter region (863 to +64 bp) cloned in front of a reporter gene, luciferase, in the presence or absence of SXR. Transfected cells were treated with CYP3A4 inducers such as rifampicin, PCN and RU 486, in order to examine the regulation of CYP3A4 gene expression in the presence or absence of trichostatin A (TSA). In Hepa-1 cells, CYP3A4 inducers increased modestly the luciferase activity when TSA was co-treated, but this increment was not enhanced by SXR cotransfection. Taken together, these results indicated that the inhibition of histone deacetylation was required to SXR-mediated increase in CYP3A4 proximal promoter region when rifampicin, or PCN was treated. Further a trans-activation by SXR may demand other species-specific transcription factors.

• Molecules and Cells
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• v.28 no.6
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• pp.553-558
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• 2009

In the periphery, a galectin-1 receptor, CD7, plays crucial roles in galectin-1-mediated apoptosis of activated T-cells as well as progression of T-lymphoma. Previously, we demonstrated that $NF-{\kappa}B$ downregulated CD7 gene expression through the p38 MAPK pathway in developing immature thymocytes. However, its regulatory pathway is not well understood in functional mature T-cells. Here, we show that CD7 expression was downregulated by Twist2 in Jurkat cells, a human acute T-cell lymphoma cell line, and in EL4 cells, a mature murine T-cell lymphoma cell line. Furthermore, ectopic expression of Twist2 in Jurkat cells reduced galectin-1-induced apoptosis. While full-length Twist2 decreased CD7 promoter activity, a C-terminal deletion form of Twist2 reversed its inhibition, suggesting an important role of the C-terminus in CD7 regulation. In addition, CD7 expression was enhanced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate, which indicates that Twist2 might be one of candidate factors involved in histone deacetylation. Based on these results, we conclude that upregulation of Twist2 increases the resistance to galectin-1-mediated-apoptosis, which may have significant implications for the progression of some T-cells into tumors such as Sezary cells.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.323.3-324
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• 2002

Histone deacetylases (HDAC) activity is associated generally with transcriptional repression. We have reported previously that apicidin. a histione deacetylase inhibitor. inhibited the proliferation of tumor cells via induction of p21 WAF/C1P1. We extended our study to identify the effect of apicidin on the expression of other cell cycle regulatory protein. such as cyclin E. a critical regulator of the transition from G1 into S phase. (omitted)

• Proceedings of the Korean Society of Veterinary Pathology Conference
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• 2003.10a
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• pp.10-10
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• 2003

Histone deacetylase (HDAC) inhibition has been demonstrated to change the expressions of a restricted set of cellular genes, T cells have an essential role in the pathogenesis of allergen-induced airway inflammation [1]. In recent studies, it has been demonstrated that treatment with HDAC inhibitors induces a T cell-suppressive effect [2]. The purpose of this study was to determine whether treatment with trichostatin A (TSA), a representative HDAC inhibitor, would reduce the allergen-induced airway inflammation in a mouse asthma model. (omitted)

• BMB Reports
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• v.41 no.11
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• pp.751-756
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• 2008

Aging and cancer both occur as a result of accumulated cellular damage, and both are related to the regulation of specific genes in the damage response. Recent research has unveiled connections between the mechanisms of aging and cancer, but how to prevent the development of cancer and increase longevity remain unknown. SIRT1 (the mammalian Sir2), which has $NAD^+$-dependent class III histone deacetylase activity, may be a key gene linking the modulation of cancer and aging. SIRT1 has broad biological functions in growth regulation, stress response, tumorigenesis, endocrine signaling, and extended lifespan. Here, we focus on the current knowledge regarding the role of SIRT1 in aging and cancer, and discuss the implications of SIRT1 as a therapeutic target for the optimal balance between anti-aging and anti-cancer activities.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.120.2-120.2
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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. (omitted)

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.144.1-144.1
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• 2003

We previously reported that the activation of p$21^{WAFl/Cip1}$ transcription by histone deacetylase inhibitor apicidin was mediated through Spl sites and pointed to the possible participation of protein kinase C (PKC). In this study, we investigated the role and identity of the specific isoforms of PKC involved and identified phosphatidylinositol 3-kinase (PI 3-kinase) as an upstream effector in HeLa cells. Using an isoform-specific pharmacological inhibitor of PKC, a PKC$\varepsilon$ dominant-negative mutant, and antisense oligonucleotide to inhibit PKC$\varepsilon$ specifically, (omitted)