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Yin Won Lee - One of the best experts on this subject based on the ideXlab platform.

  • functional characterization and manipulation of the Apicidin biosynthetic pathway in fusarium semitectum
    Molecular Microbiology, 2010
    Co-Authors: Jianming Jin, Seunghoon Lee, Jungkwan Lee, Seung Ryul Baek, Jincheol Kim, Sunghwan Yun, Sook Young Park, Seogchan Kang, Yin Won Lee
    Abstract:

    Apicidin is a cyclic tetrapeptide produced by certain isolates of Fusarium semitectum and has been shown to inhibit Apicomplexan histone deacetylase. An Apicidin-producing strain (KCTC16676) of the filamentous fungus was mutated using an Agrobacterium tumefaciens-mediated transformation, resulting in 24 Apicidin-deficient mutants. Three of the mutants had a T-DNA insertion in a gene that encodes a non-ribosomal peptide synthetase (NRPS). Results of sequence, expression, and gene deletion analyses defined an Apicidin biosynthetic gene cluster, and the NRPS gene was named as Apicidin synthetase gene 1 (APS1). A 63 kb region surrounding APS1 was sequenced and analysis revealed the presence of 19 genes. All of the genes including APS1 were individually deleted to determine their roles in Apicidin biosynthesis. Chemical analyses of the mutant strains showed that eight genes are required for Apicidin production and were used to propose an Apicidin biosynthetic pathway. The Apicidin analogues Apicidin E, Apicidin D(2) and Apicidin B were identified from chemical analysis of the mutants. The cluster gene APS2, a putative transcription factor, was shown to regulate expression of the genes in the cluster and overexpression of APS2 increased Apicidin production. This study establishes the Apicidin biosynthetic pathway and provides new opportunities to improve the production of Apicidin and produce new analogues.

  • Apicidin is a histone deacetylase inhibitor with anti invasive and anti angiogenic potentials
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Seong Hwan Kim, Yin Won Lee, Jeungwhan Han, Hoi Young Lee, Hyangwoo Lee, Sanghun Ahn, Mi Ran Kim, Kye Won Kim, Won Bae Kim, Sungyoul Hong
    Abstract:

    Apicidin has been identified as a histone deacetylase (HDAC) inhibitor. Since HDAC inhibitors are emerging as an exciting new class of potential anti-cancer agents, in the present study, we have examined the inhibitory effect of Apicidin on cancer invasion and angiogenesis. Apicidin induced di- and tri-acetylated forms of histone H4 and the morphological alteration in v-ras-transformed mouse fibroblast NIH3T3 cells. Apicidin dramatically inhibited the invasion of v-ras-NIH3T3 and human melanoma A2058 cells and it could be associated with its ability to regulate the activities of matrix metalloproteinases. Interestingly, Apicidin strongly inhibited the formation of new vessels on chorioallantoic membrane and the tube formation of ECV304 human vascular endothelial cells. This is the first report to show the anti-angiogenic potential of Apicidin and it could be developed as a new type of anti-cancer drug.

  • expression of p21 waf1 cip1 through sp1 sites by histone deacetylase inhibitor Apicidin requires pi 3 kinase pkc epsilon signaling pathway
    Oncogene, 2003
    Co-Authors: Yong Kee Kim, Yin Won Lee, Sungyoul Hong, Jeungwhan Han, Hoi Young Lee, Yun Na Woo, Jae Kwang Chun, Ji Yeon Yoo, Eunjung Cho, Hyangwoo Lee
    Abstract:

    We previously reported that the activation of p21(WAF1/Cip1) transcription by histone deacetylase inhibitor Apicidin was mediated through Sp1 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 epsilon dominant-negative mutant, and antisense oligonucleotide to inhibit PKC epsilon specifically, we found that among PKC isoforms, PKC epsilon was required for the p21(WAF1/Cip1) expression by Apicidin. In addition to PKC epsilon, PI 3-kinase appeared to participate in the activation of p21(WAF1/Cip1) promoter by Apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21(WAF1/Cip1) promoter and p21(WAF1/Cip1) protein expression by Apicidin. Furthermore, membrane translocation of PKC epsilon in response to Apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKC epsilon in the p21(WAF1/Cip1) promoter activation by Apicidin. However, the p21(WAF1/Cip1) expression by Apicidin appeared to be independent of the histone hyperacetylation, since Apicidin-induced histone hyperacetylation of p21(WAF1/Cip1) promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21(WAF1/Cip1) by Apicidin. Taken together, these results suggest that the PI 3-kinase-PKC epsilon signaling pathway plays a pivotal role in the expression of the p21(WAF1/Cip1) by Apicidin.

  • Apicidin a histone deacetylase inhibitor induces apoptosis and fas fas ligand expression in human acute promyelocytic leukemia cells
    Journal of Biological Chemistry, 2002
    Co-Authors: So Hee Kwon, Yin Won Lee, Jong Woo Yoon, Sungyoul Hong, Seong Hoon Ahn, Gyuun Bae, Hoi Young Lee, Yong Kee Kim, Hyangwoo Lee, Jeungwhan Han
    Abstract:

    We previously reported that Apicidin arrested human cancer cell growth through selective induction of p21(WAF1/Cip1). In this study, the apoptotic potential of Apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with Apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, Apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated Apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by Apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that Apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, Apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with Apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that Apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.

  • activation of p21 waf1 cip1 transcription through sp1 sites by histone deacetylase inhibitor Apicidin involvement of protein kinase c
    Journal of Biological Chemistry, 2001
    Co-Authors: Jeungwhan Han, Yin Won Lee, Jong Woo Yoon, Seong Hoon Ahn, Gyuun Bae, Hoi Young Lee, Yong Kee Kim, S H Hong, Hyangwoo Lee
    Abstract:

    We previously reported that Apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21(WAF1/Cip1). In this study, we determined the molecular mechanisms by which Apicidin induced the p21(WAF1/Cip1) gene expression in HeLa cells. Apicidin induced p21(WAF1/Cip1) mRNA independent of the de novo protein synthesis and activated the p21(WAF1/Cip1) promoter through Sp1-3 site located at -82 and -77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21(WAF1/Cip1) promoter via Sp1 sites, which was accompanied by a marked suppression of p21(WAF1/Cip1) mRNA and protein expression induced by Apicidin. Consistent with the transcriptional activation of p21(WAF1/Cip1) promoter by Apicidin, Apicidin treatment led to the translocation of PKCepsilon from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21(WAF1/Cip1) via Sp1 sites by Apicidin. However, the PKC-mediated transcriptional activation of p21(WAF1/Cip1) by Apicidin appears to be independent of the histone hyperacetylation, because Apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21(WAF1/Cip1) promoter, p21(WAF1/Cip1) mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21(WAF1/Cip1) by Apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21(WAF1/Cip1) gene by Apicidin.

Chih Yang Huang - One of the best experts on this subject based on the ideXlab platform.

  • calmodulin camkii γ mediates prosurvival capability in Apicidin persistent hepatocellular carcinoma cells via erk1 2 creb c fos signaling pathway
    Journal of Cellular Biochemistry, 2021
    Co-Authors: Weichung Hsu, Ming Cheng Chen, Yujung Lin, Tsofu Wang, Wei Wen Kuo, B Mahalakshmi, Chaouhan Hitesh Singh, Meichih Chen, Chih Yang Huang
    Abstract:

    Calmodulin (CaM), a Ca2+ binding protein, plays a critical role in cancer initiation and progression through binding and activating numerous target proteins, including Ca2+ /calmodulin-dependent protein kinase (CaMK) family proteins. However, the mechanisms underlying the effects of CaM/CaMKs on the survival capability of liver cancer cells is unclear, and this study investigates this mechanism in Apicidin-persistent HA22T cells. CaM level was upregulated, especially in the cytosol, in Apicidin-persistent HA22T cells than in parental HA22T cells and was positively associated with cell proliferation and migration capacity of Apicidin-persistent HA22T cells. Further, the expression of CaM-activated CaMKs-dependent signaling cascades, including CaMKK2, CaMKIV, CaMKII-γ, and p-CaMKII was observed in Apicidin-persistent HA22T cells, which were transiently activated by mitogen-activated protein kinase oncogenic signaling, such as CREB, ERK1/2, and c-fos. Furthermore, a specific CaM inhibitor trifluoperazine reduced the levels of p-CREB, p-ERK1/2, and c-fos in Apicidin-persistent HA22T cells than in parental HA22T cells. Additionally, inhibition of CaM also suppressed CaM-induced Bcl-XL (an antiapoptotic protein) expression in Apicidin-persistent HA22T cells. Our finding emphasizes an essential role of CaM/CaMKs in augmentation of the survival capability of Apicidin-persistent liver cancer cells and suggests that CaM inhibition significantly attenuates CaM-induced tumor growth and abrogates antiapoptotic function and also offers a promising therapeutic target for cancer treatment.

  • Apicidin resistant ha22t hepatocellular carcinoma cells massively promote pro survival capability via igf ir pi3k akt signaling pathway activation
    Tumor Biology, 2014
    Co-Authors: Hsi Hsien Hsu, Li Hao Cheng, Yueh Min Lin, Ming Cheng Chen, Nien Hung Lee, Fuu Jen Tsai, Chih Yang Huang, Wei Wen Kuo, Kun Hsi Tsai
    Abstract:

    Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of Apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in Apicidin-R cells, but Apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, Apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of Apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients.

  • activation of snail and emt like signaling via the ikkαβ nf κb pathway in Apicidin resistant ha22t hepatocellular carcinoma cells
    Chinese Journal of Physiology, 2013
    Co-Authors: Li Hao Cheng, Hsi Hsien Hsu, Li Mien Chen, Yueh Min Lin, Ming Cheng Chen, Nien Hung Lee, Fuu Jen Tsai, Chih Yang Huang
    Abstract:

    The molecular and phenotypic associations between chemo- or radio-resistance and the acquisition of epithelial-mesenchymal transition (EMT)-like phenotype are tightly related in cancer cells. Wnt/β- catenin and NF-κB signaling pathways play crucial roles in EMT induction. Apicidin-resistant (Apicidin- R) HA22T cells are known to activate the Wnt/β-catenin signaling pathway and MMP-2 expression via the IGF-IR/PI3K/Akt signaling pathway to enhance metastatic effects of cancer cells. In this study, we further investigated if Apicidin-R HA22T cells actually underwent EMT. In Apicidin-R HA22T cells, E-cadherin protein level was reduced but Vimentin, Snail and Twist were significantly activated. Activation of p-IKKαβ and p-IκBα was also observed in Apicidin-R HA22T cells. Apicidin-R HA22T cells displayed even higher NF-κB nuclear accumulation. Snail was enhanced but GSK3-β was reduced. However, unphosphorylated GSK3-β protein level was totally reversed when the Snail-specific siRNA was applied in a knockdown experiment. Taken together, Apicidin-R HA22T cells could potentiate aggressive metastasis behavior due to up-regulation of Snail expression and promoted EMT effects via the IKKαβ/NF-κB pathway. In addition, Snail might decrease the GSK3-β level resulting in extraordinarily activation of Wnt/β-catenin signaling pathway.

  • Apicidin resistant ha22t hepatocellular carcinoma cells strongly activated the wnt β catenin signaling pathway and mmp 2 expression via the igf ir pi3k akt signaling pathway enhancing cell metastatic effect
    Bioscience Biotechnology and Biochemistry, 2013
    Co-Authors: Cheng Hong Hsieh, Li Hao Cheng, Hsi Hsien Hsu, Yueh Min Lin, Ming Cheng Chen, Fuu Jen Tsai, You Liang Hsieh, Chih Yang Huang
    Abstract:

    The IGF-IR/PI3K/Akt signaling pathway inhibited GSK3-β activity by phosphorylation and this promoted β-catenin nuclear localization. Our previous study indicated that β-catenin mRNA level was significantly higher in tumor areas than in non-tumor ones, especially in late pathologic stage tumors. However, β-catenin inhibition resulted in significantly suppressed migration and invasion ability of HA22T cells. Thus, Wnt/β-catenin pathway over-activation might be involved in metastatic enhancement of Apicidin-resistant HA22T cell metastasis. Apicidin-resistant (AR) HA22T cells showed higher β-catenin nuclear accumulation and significantly decreased GSK-3-β protein level, in relation to parental cells. Results also indicated that AR cells increased abundantly in Tbx3, a downstream target of Wnt/β-catenin that it is implicated in liver cancer. AR cells also inhibited the MEK/ERK/PEA3 pathway which promoted MMP-2 activation. But, Apicidin-resistant effect was totally reversed by LY294002 and AG1024. In conclusion, Apicidin-R HA22T cells activated the Wnt/β-catenin pathway and induced, MMP-2 expression via IGF-IR/PI3K/Akt signaling further enhancing cell the metastatic effects.

Jeungwhan Han - One of the best experts on this subject based on the ideXlab platform.

  • Cell, Tumor, and Stem Cell Biology Depletion of Embryonic Stem Cell Signature by Histone Deacetylase Inhibitor in NCCIT Cells: Involvement of Nanog Suppression
    2014
    Co-Authors: Juengsoo You, Eunjung Cho, Jaeku Kang, Jae Cheol Lee, Yae Jee Jeon, Jeungwhan Han
    Abstract:

    The embryonic stem cell-like gene expression signature has been shown to be associated with poorly differentiated aggressive human tumors and has attracted great attention as a potential target for future cancer therapies. Here, we investigate the potential of the embryonic stem cell signature as molecular target for the therapy and the strategy to suppress the embryonic stem cell signature. The core stemness gene Nanog is abnormally overexpressed in human embryonic carcinoma NCCIT cells showing gene expression profiles similar to embryonic stem cells. Down-regulation of the gene by either small interfering RNAs targeting Nanog or histone deacetylase inhibitor Apicidin causes reversion of expression pattern of embryonic stem cell signature including Oct4, Sox2, and their target genes, leading to cell cycle arrest, inhibition of colony formation in soft agar, and induction of differentiation into all three germ layers. These effects are antagonized by reintroduction of Nanog. Interestingly, embryonic carcinoma cells (NCCIT, NTERA2, and P19) exhibit a higher sensitivity to Apicidin in down-regulation of Nanog compared with embryonic stem cells. Furthermore, the down-regulation of Nanog expression by Apicidin is mediated by a coordinated change in recruitment of epigenetic modulators and transcription factors to the promoter region. These findings indicate that overexpression of stemness gene Nanog in NCCIT cells is associated with maintaining stem cell-like phenotype and suggest that targeting Nanog might be an approach for improved therapy of poorly differentiated tumors. [Cancer Res 2009;69(14):5716–25

  • histone deacetylase inhibitor Apicidin mediated drug resistance involvement of p glycoprotein
    Biochemical and Biophysical Research Communications, 2008
    Co-Authors: Yong Kee Kim, Wahn Soo Choi, Jeungwhan Han, Dongwan Seo, Hoi Young Lee, Nam Hyun Kim, Jee Won Hwang, Yongjin Song, Yeonsuk Park, Sunam Kim
    Abstract:

    Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor Apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, Apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, Apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of Apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by Apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that Apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors.

  • involvement of hdac1 and the pi3k pkc signaling pathways in nf κb activation by the hdac inhibitor Apicidin
    Biochemical and Biophysical Research Communications, 2006
    Co-Authors: Yong Kee Kim, Jeungwhan Han, Dongwan Seo, Hoi Young Lee, Dongwon Kang, Sunam Kim
    Abstract:

    Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor Apicidin. Treatment of HeLa cells with Apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by Apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by Apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, Apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by Apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of Apicidin.

  • development of a liquid chromatography electrospray tandem mass spectrometry assay for the quantification of Apicidin a novel histone deacetylase inhibitor in rat serum application to a pharmacokinetic study
    Rapid Communications in Mass Spectrometry, 2005
    Co-Authors: Beom Soo Shin, Eun Hye Park, Chi Ho Yoon, John Kim, Jeungwhan Han, Chulhwan Kim, Sun Dong Yoo
    Abstract:

    Apicidin, a fungal metabolite isolated from Fusarium pallidoroseum, is a cyclic tetrapeptide that exhibits potent anti-protozoal and anti-angiogenic activities. Although extensive studies have been recently conducted to examine the biological and pharmacological action, no information is available on the quantitative analysis of Apicidin. To our knowledge, this study is the first to describe a rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay method for the quantification of Apicidin in rat serum. The method was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transitions m/z 624.7  84.3 and 372.1  176.1 for Apicidin and trazodone, respectively. The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 0.5 ng/mL using 0.1 mL of rat serum. The assay was linear over a range from 0.5–1000 ng/mL, with correlation coefficients >0.9994. The mean intra- and inter-day assay accuracy ranged from 99.9–101.5% and 94.8–102.1%, respectively, and the mean intra- and inter-day precision was between 2.7–5.9% and 1.6–11.5%, respectively. The developed assay method was applied to a pharmacokinetic study after intravenous injection of Apicidin in rats at a dose of 1 mg/kg. Copyright © 2005 John Wiley & Sons, Ltd.

  • Apicidin is a histone deacetylase inhibitor with anti invasive and anti angiogenic potentials
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Seong Hwan Kim, Yin Won Lee, Jeungwhan Han, Hoi Young Lee, Hyangwoo Lee, Sanghun Ahn, Mi Ran Kim, Kye Won Kim, Won Bae Kim, Sungyoul Hong
    Abstract:

    Apicidin has been identified as a histone deacetylase (HDAC) inhibitor. Since HDAC inhibitors are emerging as an exciting new class of potential anti-cancer agents, in the present study, we have examined the inhibitory effect of Apicidin on cancer invasion and angiogenesis. Apicidin induced di- and tri-acetylated forms of histone H4 and the morphological alteration in v-ras-transformed mouse fibroblast NIH3T3 cells. Apicidin dramatically inhibited the invasion of v-ras-NIH3T3 and human melanoma A2058 cells and it could be associated with its ability to regulate the activities of matrix metalloproteinases. Interestingly, Apicidin strongly inhibited the formation of new vessels on chorioallantoic membrane and the tube formation of ECV304 human vascular endothelial cells. This is the first report to show the anti-angiogenic potential of Apicidin and it could be developed as a new type of anti-cancer drug.

Hyangwoo Lee - One of the best experts on this subject based on the ideXlab platform.

  • histone deacetylase inhibitor Apicidin induces cyclin e expression through sp1 sites
    Biochemical and Biophysical Research Communications, 2006
    Co-Authors: Soyoung Kim, Seong Hoon Ahn, Dongwan Seo, Yong Kee Kim, Eunjung Cho, Jaeku Kang, Jae Cheol Lee, Changhee Lee, Juengsoo You, Hyangwoo Lee
    Abstract:

    We show that a histone deacetylase (HDAC) inhibitor Apicidin increases the transcriptional activity of cyclin E gene, which results in accumulation of cyclin E mRNA and protein in a time- and dose-dependent manner. Interestingly, Apicidin induction of cyclin E gene is found to be mediated by Sp1- rather than E2F-binding sites in the cyclin E promoter, as evidenced by the fact that specific inhibition of Sp1 leads to a decrease in Apicidin activation of cyclin E promoter activity and protein expression, but mutation of E2F-binding sites of cyclin E promoter region fails to inhibit the ability of Apicidin to activate cyclin E transcription. In addition, this transcriptional activation of cyclin E by Apicidin is associated with histone hyperacetylation of cyclin E promoter region containing Sp1-binding sites. Our results demonstrate that regulation of histone modification by an HDAC inhibitor Apicidin contributes to induction of cyclin E expression and this effect is Sp1-dependent.

  • Apicidin is a histone deacetylase inhibitor with anti invasive and anti angiogenic potentials
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Seong Hwan Kim, Yin Won Lee, Jeungwhan Han, Hoi Young Lee, Hyangwoo Lee, Sanghun Ahn, Mi Ran Kim, Kye Won Kim, Won Bae Kim, Sungyoul Hong
    Abstract:

    Apicidin has been identified as a histone deacetylase (HDAC) inhibitor. Since HDAC inhibitors are emerging as an exciting new class of potential anti-cancer agents, in the present study, we have examined the inhibitory effect of Apicidin on cancer invasion and angiogenesis. Apicidin induced di- and tri-acetylated forms of histone H4 and the morphological alteration in v-ras-transformed mouse fibroblast NIH3T3 cells. Apicidin dramatically inhibited the invasion of v-ras-NIH3T3 and human melanoma A2058 cells and it could be associated with its ability to regulate the activities of matrix metalloproteinases. Interestingly, Apicidin strongly inhibited the formation of new vessels on chorioallantoic membrane and the tube formation of ECV304 human vascular endothelial cells. This is the first report to show the anti-angiogenic potential of Apicidin and it could be developed as a new type of anti-cancer drug.

  • expression of p21 waf1 cip1 through sp1 sites by histone deacetylase inhibitor Apicidin requires pi 3 kinase pkc epsilon signaling pathway
    Oncogene, 2003
    Co-Authors: Yong Kee Kim, Yin Won Lee, Sungyoul Hong, Jeungwhan Han, Hoi Young Lee, Yun Na Woo, Jae Kwang Chun, Ji Yeon Yoo, Eunjung Cho, Hyangwoo Lee
    Abstract:

    We previously reported that the activation of p21(WAF1/Cip1) transcription by histone deacetylase inhibitor Apicidin was mediated through Sp1 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 epsilon dominant-negative mutant, and antisense oligonucleotide to inhibit PKC epsilon specifically, we found that among PKC isoforms, PKC epsilon was required for the p21(WAF1/Cip1) expression by Apicidin. In addition to PKC epsilon, PI 3-kinase appeared to participate in the activation of p21(WAF1/Cip1) promoter by Apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21(WAF1/Cip1) promoter and p21(WAF1/Cip1) protein expression by Apicidin. Furthermore, membrane translocation of PKC epsilon in response to Apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKC epsilon in the p21(WAF1/Cip1) promoter activation by Apicidin. However, the p21(WAF1/Cip1) expression by Apicidin appeared to be independent of the histone hyperacetylation, since Apicidin-induced histone hyperacetylation of p21(WAF1/Cip1) promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21(WAF1/Cip1) by Apicidin. Taken together, these results suggest that the PI 3-kinase-PKC epsilon signaling pathway plays a pivotal role in the expression of the p21(WAF1/Cip1) by Apicidin.

  • Apicidin a histone deacetylase inhibitor induces apoptosis and fas fas ligand expression in human acute promyelocytic leukemia cells
    Journal of Biological Chemistry, 2002
    Co-Authors: So Hee Kwon, Yin Won Lee, Jong Woo Yoon, Sungyoul Hong, Seong Hoon Ahn, Gyuun Bae, Hoi Young Lee, Yong Kee Kim, Hyangwoo Lee, Jeungwhan Han
    Abstract:

    We previously reported that Apicidin arrested human cancer cell growth through selective induction of p21(WAF1/Cip1). In this study, the apoptotic potential of Apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with Apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, Apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated Apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by Apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that Apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, Apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with Apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that Apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.

  • activation of p21 waf1 cip1 transcription through sp1 sites by histone deacetylase inhibitor Apicidin involvement of protein kinase c
    Journal of Biological Chemistry, 2001
    Co-Authors: Jeungwhan Han, Yin Won Lee, Jong Woo Yoon, Seong Hoon Ahn, Gyuun Bae, Hoi Young Lee, Yong Kee Kim, S H Hong, Hyangwoo Lee
    Abstract:

    We previously reported that Apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21(WAF1/Cip1). In this study, we determined the molecular mechanisms by which Apicidin induced the p21(WAF1/Cip1) gene expression in HeLa cells. Apicidin induced p21(WAF1/Cip1) mRNA independent of the de novo protein synthesis and activated the p21(WAF1/Cip1) promoter through Sp1-3 site located at -82 and -77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21(WAF1/Cip1) promoter via Sp1 sites, which was accompanied by a marked suppression of p21(WAF1/Cip1) mRNA and protein expression induced by Apicidin. Consistent with the transcriptional activation of p21(WAF1/Cip1) promoter by Apicidin, Apicidin treatment led to the translocation of PKCepsilon from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21(WAF1/Cip1) via Sp1 sites by Apicidin. However, the PKC-mediated transcriptional activation of p21(WAF1/Cip1) by Apicidin appears to be independent of the histone hyperacetylation, because Apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21(WAF1/Cip1) promoter, p21(WAF1/Cip1) mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21(WAF1/Cip1) by Apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21(WAF1/Cip1) gene by Apicidin.

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  • histone deacetylase inhibitor Apicidin mediated drug resistance involvement of p glycoprotein
    Biochemical and Biophysical Research Communications, 2008
    Co-Authors: Yong Kee Kim, Wahn Soo Choi, Jeungwhan Han, Dongwan Seo, Hoi Young Lee, Nam Hyun Kim, Jee Won Hwang, Yongjin Song, Yeonsuk Park, Sunam Kim
    Abstract:

    Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor Apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, Apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, Apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of Apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by Apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that Apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors.

  • activation of nf kappab by hdac inhibitor Apicidin through sp1 dependent de novo protein synthesis its implication for resistance to apoptosis
    Cell Death & Differentiation, 2006
    Co-Authors: Yong Kee Kim, Dongwan Seo, Juengsoo You, Sunam Kim, Euikyung Lee, Jaeheon Kang, Jie Ae Kim, Jungnam Park, J W Hwang, Hoi Young Lee
    Abstract:

    Histone deacetylase (HDAC) inhibitors are promising anti-cancer drugs, but these exert differential responses depending on the cell types. Here, we demonstrate a new mechanism for activation of nuclear factor-kappaB (NF-kappaB) by HDAC inhibitor Apicidin and the role of NF-kappaB signaling pathway for mediating differential cellular responses, especially, apoptosis. Treatment of HeLa cells with Apicidin increases transcriptional activity of NF-kappaB and its target gene IL-8 and cIAP-1 induction, which involves the activation of IKK-IkappaBalpha signaling pathway through Sp1-dependent de novo protein synthesis. In parallel, Apicidin treatment leads to histone hyperacetylation in the IL-8 promoter region independent of NF-kappaB signaling pathway, which is not sufficient for full transcription of IL-8 gene. This NF-kappaB activation contributes to resistance of HeLa cells to apoptotic potential of Apicidin. Collectively, our results suggest that activation of NF-kappaB signaling cascade functions as a critical modulator to determine cell fate on apoptosis in response to HDAC inhibitors.

  • involvement of hdac1 and the pi3k pkc signaling pathways in nf κb activation by the hdac inhibitor Apicidin
    Biochemical and Biophysical Research Communications, 2006
    Co-Authors: Yong Kee Kim, Jeungwhan Han, Dongwan Seo, Hoi Young Lee, Dongwon Kang, Sunam Kim
    Abstract:

    Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-kappaB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-kappaB activation in response to the HDAC inhibitor Apicidin. Treatment of HeLa cells with Apicidin leads to an increase in transcriptional activity of NF-kappaB and the expression of its target genes, IL-8 and TNF-alpha. TNF-alpha expression by Apicidin is induced at earlier time points than NF-kappaB activation or IL-8 expression. In addition, our data show that the early expression of TNF-alpha does not lead to activation of NF-kappaB, because disruption of TNF-alpha activity by a neutralizing antibody does not affect nuclear translocation of NF-kappaB, IkappaBalpha degradation or reporter gene activation by Apicidin. However, this activation of NF-kappaB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, Apicidin activation of NF-kappaB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-kappaB reporter gene activity. Collectively, our results suggest that activation of NF-kappaB signaling by Apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of Apicidin.

  • Apicidin is a histone deacetylase inhibitor with anti invasive and anti angiogenic potentials
    Biochemical and Biophysical Research Communications, 2004
    Co-Authors: Seong Hwan Kim, Yin Won Lee, Jeungwhan Han, Hoi Young Lee, Hyangwoo Lee, Sanghun Ahn, Mi Ran Kim, Kye Won Kim, Won Bae Kim, Sungyoul Hong
    Abstract:

    Apicidin has been identified as a histone deacetylase (HDAC) inhibitor. Since HDAC inhibitors are emerging as an exciting new class of potential anti-cancer agents, in the present study, we have examined the inhibitory effect of Apicidin on cancer invasion and angiogenesis. Apicidin induced di- and tri-acetylated forms of histone H4 and the morphological alteration in v-ras-transformed mouse fibroblast NIH3T3 cells. Apicidin dramatically inhibited the invasion of v-ras-NIH3T3 and human melanoma A2058 cells and it could be associated with its ability to regulate the activities of matrix metalloproteinases. Interestingly, Apicidin strongly inhibited the formation of new vessels on chorioallantoic membrane and the tube formation of ECV304 human vascular endothelial cells. This is the first report to show the anti-angiogenic potential of Apicidin and it could be developed as a new type of anti-cancer drug.

  • expression of p21 waf1 cip1 through sp1 sites by histone deacetylase inhibitor Apicidin requires pi 3 kinase pkc epsilon signaling pathway
    Oncogene, 2003
    Co-Authors: Yong Kee Kim, Yin Won Lee, Sungyoul Hong, Jeungwhan Han, Hoi Young Lee, Yun Na Woo, Jae Kwang Chun, Ji Yeon Yoo, Eunjung Cho, Hyangwoo Lee
    Abstract:

    We previously reported that the activation of p21(WAF1/Cip1) transcription by histone deacetylase inhibitor Apicidin was mediated through Sp1 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 epsilon dominant-negative mutant, and antisense oligonucleotide to inhibit PKC epsilon specifically, we found that among PKC isoforms, PKC epsilon was required for the p21(WAF1/Cip1) expression by Apicidin. In addition to PKC epsilon, PI 3-kinase appeared to participate in the activation of p21(WAF1/Cip1) promoter by Apicidin, since inactivation of PI 3-kinase either by transient expression of dominant-negative mutant of PI 3-kinase or its specific inhibitors, LY294002 and wortmannin, attenuated the activation of p21(WAF1/Cip1) promoter and p21(WAF1/Cip1) protein expression by Apicidin. Furthermore, membrane translocation of PKC epsilon in response to Apicidin was blocked by the PI 3-kinase inhibitor, indicating the role of PI 3-kinase as an upstream molecule of PKC epsilon in the p21(WAF1/Cip1) promoter activation by Apicidin. However, the p21(WAF1/Cip1) expression by Apicidin appeared to be independent of the histone hyperacetylation, since Apicidin-induced histone hyperacetylation of p21(WAF1/Cip1) promoter region was not affected by inhibition of PI 3-kinase and PKC, suggesting that the chromatin remodeling through the histone hyperacetylation alone might not be sufficient for the expression of p21(WAF1/Cip1) by Apicidin. Taken together, these results suggest that the PI 3-kinase-PKC epsilon signaling pathway plays a pivotal role in the expression of the p21(WAF1/Cip1) by Apicidin.