• Genomics & Informatics
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• v.14 no.3
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• pp.78-84
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• 2016

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

• IMMUNE NETWORK
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• v.14 no.6
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• pp.321-327
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• 2014

TGF-${\beta}$ induces IgA class switching by B cells. We previously reported that Smad3 and Smad4, pivotal TGF-${\beta}$ signal-transducing transcription factors, mediate germline (GL) ${\alpha}$ transcription induced by TGF-${\beta}1$, resulting in IgA switching by mouse B cells. Post-translational sumoylation of Smad3 and Smad4 regulates TGF-${\beta}$-induced transcriptional activation in certain cell types. In the present study, we investigated the effect of sumoylation on TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ transcription and IgA switching by mouse B cell line, CH12F3-2A. Overexpression of small ubiquitin-like modifier (SUMO)-1, SUMO-2 or SUMO-3 did not affect TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ promoter activity, expression of endogenous $GL{\alpha}$ transcripts, surface IgA expression, and IgA production. Next, we tested the effect of the E3 ligase PIASy on TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ promoter activity. We found that PIASy overexpression suppresses the $GL{\alpha}$ promoter activity in cooperation with histone deacetylase 1. Taken together, these results suggest that SUMO itself does not affect regulation of $GL{\alpha}$ transcription and IgA switching induced by TGF-${\beta}1$/Smad3/4, while PIASy acts as a repressor.

• Molecules and Cells
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• v.38 no.10
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• pp.859-865
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• 2015

Most imprinted genes are concerned with embryonic development, especially placental development. Here, we identified a placenta-specific imprinted gene Qpct. Our results show that Qpct is widely expressed during early embryonic development and can be detected in the telecephalon, midbrain, and rhombencephalon at E9.5-E11.5. Moreover, Qpct is strikingly expressed in the brain, lung and liver in E15.5. Expression signals for Qpct achieved a peak at E15.5 during placental development and were only detected in the labyrinth layer in E15.5 placenta. ChIP assay results suggest that the modification of histone H3K4me3 can result in maternal activating of Qpct.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.6
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• pp.493-502
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• 2020

Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G₂/M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio. ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.

• Journal of Veterinary Clinics
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• v.34 no.1
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• pp.27-33
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• 2017

Although HDACIs affect ubiquitously expressed histone deacetylase and increase cellular senescence, there has been little study on the effect of age on treatment with HDACIs. Accordingly, the purpose of this study was to compare cellular senescence status and vorinostat-induced senescence in fibroblasts derived from aged dogs compared to young dogs. Skin tissues were taken from young (1-year-old) and aged (7-year-old) male dogs, and fibroblasts were cultured without (control) or with 10 uM of vorinostat for 24 hr. Beta-galactosidase activity was assessed, and real-time polymerase chain reaction and western blotting were performed to analyze the expression levels of transcripts and proteins related to cellular senescence. Beta-galactosidase activity was higher in aged dogs compared to young dogs in the control group, and was increased by vorinostat treatment. Expression of p21, p53 and p16 transcripts was higher in the aged than in the young group, and all transcripts were affected by vorinostat in both young and aged groups. Western blot results showed lower H3K9 acetylation in the aged dogs compared to the young dogs, and the acetylation was increased by vorinostat treatment in both groups. However, there was no significant difference between the transcript or protein alterations induced by vorinostat.

• Korean Journal of Medicinal Crop Science
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• v.26 no.4
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• pp.302-307
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• 2018

Background: A soil-borne pathogenic fungus, Ilyonectria radicicola (Cylindrocarpon destructans) causes root rot on ginseng (Panax ginseng C. A. Meyer) and is known to attack many other plants. The Nectria/Neonectria radicicola complex has been renamed as the I. radicicola complex after analysis of its multi-gene relatedness and morphological characteristics. The fungi in this complex have been reclassified into 16 species under the genus Ilyonectria based on characteristics analysis Methods and Results: To obtain useful data from the Korean ginseng root rot, I. radicicola was isolated from the rhizosphere soils of the chestnut tree. They were identified through a pathogenicity test and a survey of the morphological features. The existence of I. radicicola in soil samples was confirmed by PCR detections using nested PCR with species-specific primer sets. These were subsequenctly isolated on semi-selective media from PCR-positive soils. Genetic analysis of the I. radicicola complex containing these pathogens was done by comparing the DNA sequences of the histone h3 region. These isolates originating from the rhizosphere soils of chestnut constituted a clade with other closely related species or I. radicicola isolates originating from ginseng or other host plants, respectively. Additionally, the pathogenicity tests to analyze the characteristics of these I. radicicola isolates revealed that they caused weakly virulent root rot on ginseng. Conclusions: This is the first study reporting that I. radicicola isolates from chestnut rhizosphere soils can attack ginseng plant in Korea. Thus, these results are expected to provide informations in the selection of suitable fields for ginseng cultivation.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.313-319
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• 2012

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity ($IC_{50}$ = 0.585 nM) inMDA-MB-231 human breast cancer cells. IN-2001 caused a significant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231human breast cancer cells. Cell cycle analysis revealed that the growth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at $G_0/G_1$ and/or $G_2$/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors $p21^{WAF1}$ and $p27^{KIP1}$ cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these findings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.

• Journal of Life Science
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• v.10 no.2
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• pp.39-44
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• 2000

Trichostatin A (TSA) is a Streptomyces product, which inhibits the enzyme activity of histone deacetylase. It is also known as an inducer of apoptosis in several human cancer cell lines. In this study, we investigated the mechanism of apoptosis induced by TSA in MDA-MB-231 human breast carcinoma cells. The cytotoxicity of TSA on MDA-MB-231 cells was assessed by MTT assay. The cell viability was decreased dose-dependently and the IC\ulcorner value was about 100 ng/ml after 48 h treatment with TSA. Morphological change and DNA ladder formation, the biochemical hallmarks of apoptotic cell death, were observed after treatment of TSA in a concentration-dependent manner, which was accompanied with cleavage of poly(ADP-ribose) polymerase and $\beta$-catenin, and activation of caspase-3. TSA treatment up-regulated the expression of a cyclin-dependent kinase inhibitor p21 (Wafl/Cip1) protein, a key regulatory protein of the cell cycle. However, there is no detectable change of both Bcl-2 and Bax expressions. These results demonstrated that TSA might inhibit cell growth through apoptosis in human breast carcinoma MDA-MB-231 cells.

• Journal of Korean Neurosurgical Society
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• v.53 no.6
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• pp.337-341
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• 2013

Objective : After spinal cord injury (SCI), functional and structural reorganization occurs at multiple levels of brain including motor cortex. However, the underlying mechanism still remains unclear. The current study was performed to investigate the alterations in the expression of the main regulators of neuronal development, survival and death, in the brain following thoracic contusive SCI in a mouse model. Methods : Eight-week-old female imprinting control region mice (n=60; 30-35 g) were used in this study. We analyzed the expression levels of regulators such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) and histone deacetylase (HDAC) 1 in the brain following thoracic contusive SCI. Results : The expression of BDNF levels were elevated significantly compared with control group at 2 weeks after injury (p<0.05). The expression of NGF levels were elevated at 2, 4 weeks compared with control group, but these difference were not significant (p>0.05). The GDNF levels were elevated at 2 week compared with control group, but these differences were not significant (p>0.05). The difference of HDAC1 levels were not significant at 2, 4 and 8 weeks compared with control group (p>0.05). Conclusion : These results demonstrate that the upregulation of BDNF may play on important role in brain reorganization after SCI.

• Journal of Microbiology and Biotechnology
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• v.31 no.10
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• pp.1358-1365
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• 2021

To clarify the role of long intergenic nonprotein-coding RNA 1232 (LINC01232) in the progression of gastric cancer and the potential mechanism, we analyzed the expression of LINC01232 in TCGA database using the GEPIA online tool, and the LINC01232 level in gastric cancer cell lines was detected by quantitative real time-polymerase chain reaction (qRT-PCR) as well. Cell proliferation assay, colony formation assay, transwell assay and tumor formation experiment in nude mice were conducted to observe the biological behavior changes of gastric cancer cells through the influence of LINC01232 knockdown. LncATLAS database and subcellular isolation assay were used for subcellular distribution of LINC01232 in gastric cancer cells. The interaction among LINC01232, zeste homolog 2 (EZH2) and kruppel-like factor 2 (KLF2) was clarified by RNA-protein interaction prediction (RPISeq), RNA immunoprecipitation (RIP), qRT-PCR and chromatin immunoprecipitation (ChIP) assay. Rescue experiments were further conducted to elucidate the biological function of LINC01232/KLF2 axis in the progression of gastric cancer. LINC01232 was upregulated in stomach adenocarcinoma (STAD) tissues and gastric cancer lines. LINC01232 knockdown inhibited the proliferative capacities of gastric cancer cells in vitro, and impaired in vivo tumorigenicity. LINC01232 was mainly distributed in the cell nucleus where it epigenetically repressed KLF2 expression via binding to the enhancer of EZH2, which was capable of binding to promoter regions of KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). LINC01232 exerts oncogenic activities in gastric cancer via inhibition of KLF2, and therefore, the knockdown of KLF2 could reverse the regulatory effect of LINC01232 in the proliferative ability of gastric cancer cells.