Publications by authors named "Hyun Seung Ban"

61 Publications

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2016-2020).

Expert Opin Ther Pat 2021 Jan 29:1-11. Epub 2021 Jan 29.

cLaboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology , Yokohama, Japan.

: Hypoxia-inducible factor (HIF) is a master regulator of oxygen homeostasis. The increased expression of genes targeted by HIF is associated with many human diseases, including ischemic cardiovascular disease, stroke, chronic lung disease, and cancer. : This patent survey summarizes the information about patented HIF inhibitors over the last 5 years. : HIF inhibitors have shown promise for the treatment of hypoxic pulmonary hypertension, a circadian rhythm disorder, calcific aortic valve disease, cerebrovascular accident, and heterotopic ossification. In addition, HIF-2α inhibitors can be used for the treatment or prevention of iron overload disorders, Crohn's disease, ulcerative colitis, and thyroid eye disease, or to improve muscle generation and repair. PT2385 completed phase I clinical trials for the treatment of clear cell renal cell carcinoma. It exerted a higher synergistic inhibitory effect on tumor growth in combination with anti-PD-1 antibody, in comparison with each treatment alone, indicating that effective immunotherapy for solid tumors counteracts of the immunosuppression induced by hypoxia. Therefore, considering the effects of hypoxia on cancer cells, stromal cells, and effector immune cells, it is important to develop inhibitors of molecular pathways activated by hypoxia for successful treatments.
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http://dx.doi.org/10.1080/13543776.2021.1874345DOI Listing
January 2021

Long-term depletion of Cereblon induces mitochondrial dysfunction in cancer cells.

BMB Rep 2021 Jan 7. Epub 2021 Jan 7.

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.

Cereblon (CRBN) is a multi-functional protein that acts as a substrate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells.
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January 2021

Licochalcone A inhibits hypoxia-inducible factor-1α accumulation by suppressing mitochondrial respiration in hypoxic cancer cells.

Biomed Pharmacother 2021 Jan 4;133:111082. Epub 2020 Dec 4.

Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea. Electronic address:

Hypoxia-inducible factor (HIF)-1 is an important regulator of the cellular response in the hypoxic tumor environment. While searching for HIF inhibitors derived from natural products that act as anticancer agents, we found that Glycyrrhiza uralensis exerts HIF-1 inhibitory activity in hypoxic cancer cells. Among the five components of G. uralensis, licochalcone A was found to potently suppress hypoxia-induced HIF-1α accumulation and expression of HIF-1α target genes, including GLUT1 and PDK1 in HCT116 cells. Licochalcone A also enhances intracellular oxygen content by directly inhibiting mitochondrial respiration, resulting in oxygen-dependent HIF-1α degradation. Hence, licochalcone A may effectively inhibit ATP production, primarily by reducing the mitochondrial respiration-mediated ATP production rate rather than the glycolysis-mediated ATP production rate. This effect subsequently suppresses cancer cell viability, including that of HCT116, H1299, and H322 cells. Consequently, these results suggest that licochalcone A has therapeutic potential in hypoxic cancer cells.
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http://dx.doi.org/10.1016/j.biopha.2020.111082DOI Listing
January 2021

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation.

Exp Mol Med 2020 11 25;52(11):1845-1856. Epub 2020 Nov 25.

College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Korea.

Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.
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http://dx.doi.org/10.1038/s12276-020-00523-5DOI Listing
November 2020

Epigenetic Associations between lncRNA/circRNA and miRNA in Hepatocellular Carcinoma.

Cancers (Basel) 2020 Sep 14;12(9). Epub 2020 Sep 14.

Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.

The three major members of non-coding RNAs (ncRNAs), named microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in hepatocellular carcinoma (HCC) development. Recently, the competing endogenous RNA (ceRNA) regulation model described lncRNA/circRNA as a sponge for miRNAs to indirectly regulate miRNA downstream target genes. Accumulating evidence has indicated that ceRNA regulatory networks are associated with biological processes in HCC, including cancer cell growth, epithelial to mesenchymal transition (EMT), metastasis, and chemoresistance. In this review, we summarize recent discoveries, which are specific ceRNA regulatory networks (lncRNA/circRNA-miRNA-mRNA) in HCC and discuss their clinical significance.
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http://dx.doi.org/10.3390/cancers12092622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565033PMC
September 2020

High-Performance Conducting Polymer Nanotube-based Liquid-Ion Gated Field-Effect Transistor Aptasensor for Dopamine Exocytosis.

Sci Rep 2020 02 28;10(1):3772. Epub 2020 Feb 28.

Infectious Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

In this study, ultrasensitive and precise detection of a representative brain hormone, dopamine (DA), was demonstrated using functional conducting polymer nanotubes modified with aptamers. A high-performance aptasensor was composed of interdigitated microelectrodes (IMEs), carboxylated polypyrrole nanotubes (CPNTs) and DA-specific aptamers. The biosensors were constructed by sequential conjugation of CPNTs and aptamer molecules on the IMEs, and the substrate was integrated into a liquid-ion gating system surrounded by pH 7.4 buffer as an electrolyte. To confirm DA exocytosis based on aptasensors, DA sensitivity and selectivity were monitored using liquid-ion gated field-effect transistors (FETs). The minimum detection level (MDL; 100 pM) of the aptasensors was determined, and their MDL was optimized by controlling the diameter of the CPNTs owing to their different capacities for aptamer introduction. The MDL of CPNT aptasensors is sufficient for discriminating between healthy and unhealthy individuals because the total DA concentration in the blood of normal person is generally determined to be ca. 0.5 to 6.2 ng/mL (3.9 to 40.5 nM) by high-performance liquid chromatography (HPLC) (this information was obtained from a guidebook "Evidence-Based Medicine 2018 SCL " which was published by Seoul Clinical Laboratory). The CPNTs with the smaller diameters (CPNT2: ca. 120 nm) showed 100 times higher sensitivity and selectivity than the wider CPNTs (CPNT1: ca. 200 nm). Moreover, the aptasensors based on CPNTs had excellent DA discrimination in the presence of various neurotransmitters. Based on the excellent sensing properties of these aptasensors, the DA levels of exogeneous DA samples that were prepared from PC12 cells by a DA release assay were successfully measured by DA kits, and the aptasensor sensing properties were compared to those of standard DA reagents. Finally, the real-time response values to the various exogeneous DA release levels were similar to those of a standard DA aptasensor. Therefore, CPNT-based aptasensors provide efficient and rapid DA screening for neuron-mediated genetic diseases such as Parkinson's disease.
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http://dx.doi.org/10.1038/s41598-020-60715-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048782PMC
February 2020

Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer.

Biochem Biophys Res Commun 2020 03 14;523(3):726-732. Epub 2020 Jan 14.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, 226-8503, Japan. Electronic address:

Betulinic acid (BA) exhibits various biological activities such as anti-bacterial, anti-inflammatory, anti-human papilloma virus (HPV), and anti-cancer activities. HPV infection is associated with a high risk of cervical cancer, which is the leading cause of deaths among women worldwide. Therefore, BA is an attractive therapeutic agent for treating cervical cancer. In this study, we investigated the role of BA in regulating the hypoxia-mediated response in HeLa cells and clarified the underlying mechanism of action. We found that BA inhibited the hypoxia-induced accumulation of HIF-1α without affecting HIF-1α mRNA levels and suppressed the expression of HIF target genes, including VEGF, GLUT1, and PDK1 in HeLa cells. Additionally, BA enhanced the β1, β2, and β5 activities of the proteasome, which resulted in reduced levels of ubiquitinated proteins and HIF-1α protein in HeLa cells. However, BA treatment did not affect the deubiquitinase enzyme activity in HeLa cells. These results indicate that inhibition of HIF-1α accumulation by BA is mediated by activation of the proteasome, and BA is a potential anticancer agent for the regulation of the HIF signaling pathway.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.031DOI Listing
March 2020

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer.

Genes (Basel) 2019 12 4;10(12). Epub 2019 Dec 4.

Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.

Hypoxia-inducible factors (HIFs) are transcription factors that play central roles in cellular responses against hypoxia. In most cancers, HIFs are closely associated with tumorigenesis by regulating cell survival, angiogenesis, metastasis, and adaptation to the hypoxic tumor microenvironment. Recently, non-coding RNAs (ncRNAs) have been reported to play critical roles in the hypoxic response in various cancers. Here, we review the roles of hypoxia-response ncRNAs in gastrointestinal cancer, with a particular focus on microRNAs and long ncRNAs, and discuss the functional relationships and regulatory mechanisms between HIFs and ncRNAs.
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http://dx.doi.org/10.3390/genes10121008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947354PMC
December 2019

PI3K/AKT/β-Catenin Signaling Regulates Vestigial-Like 1 Which Predicts Poor Prognosis and Enhances Malignant Phenotype in Gastric Cancer.

Cancers (Basel) 2019 Dec 3;11(12). Epub 2019 Dec 3.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Korea.

Although gastric cancer is a common cause of cancer mortality worldwide, its biological heterogeneity limits the available therapeutic options. Therefore, identifying novel therapeutic targets for developing effective targeted therapy of gastric cancer is a pressing need. Here, we investigate molecular function and regulatory mechanisms of () in gastric cancer. Microarray analysis of 556 gastric cancer tissues revealed that VGLL1 was a prognostic biomarker that correlated with PI3KCA and PI3KCB. regulates the proliferation of gastric cancer cells, as shown in live cell imaging, sphere formation, and in vivo xenograft model. Tail vein injection of NUGC3 cells expressing sh resulted in less lung metastasis occurring when compared to the control. In contrast, larger metastatic lesions in lung and liver were detected in the -overexpressing NUGC3 cell xenograft excision mouse model. Importantly, expression is transcriptionally regulated by the PI3K-AKT-β-catenin pathway. Subsequently, MMP9, a key molecule in gastric cancer, was explored as one of target genes that were transcribed by VGLL1-TEAD4 complex, a component of the transcription factor. Taken together, PI3K/AKT/β-catenin signaling regulates the transcription of , which promotes the proliferation and metastasis in gastric cancer. This finding suggests VGLL1 as a novel prognostic biomarker and a potential therapeutic target.
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http://dx.doi.org/10.3390/cancers11121923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966677PMC
December 2019

Epigenetic Alterations of Heat Shock Proteins (HSPs) in Cancer.

Int J Mol Sci 2019 Sep 25;20(19). Epub 2019 Sep 25.

Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.

Heat shock proteins (HSPs) are associated with various physiological processes (protein refolding and degradation) involved in the responses to cellular stress, such as cytotoxic agents, high temperature, and hypoxia. HSPs are overexpressed in cancer cells and play roles in their apoptosis, invasion, proliferation, angiogenesis, and metastasis. The regulation or translational modification of HSPs is recognized as a therapeutic target for the development of anticancer drugs. Among the regulatory processes associated with HSP expression, the epigenetic machinery (miRNAs, histone modification, and DNA methylation) has key functions in cancer. Moreover, various epigenetic modifiers of HSP expression have also been reported as therapeutic targets and diagnostic markers of cancer. Thus, in this review, we describe the epigenetic alterations of HSP expression in cancer cells and suggest that HSPs be clinically applied as diagnostic and therapeutic markers in cancer therapy via controlled epigenetic modifiers.
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http://dx.doi.org/10.3390/ijms20194758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801855PMC
September 2019

The Epigenetic Regulation of HCC Metastasis.

Int J Mol Sci 2018 Dec 10;19(12). Epub 2018 Dec 10.

Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.

Epigenetic alterations, such as histone modification, DNA methylation, and miRNA-mediated processes, are critically associated with various mechanisms of proliferation and metastasis in several types of cancer. To overcome the side effects and limited effectiveness of drugs for cancer treatment, there is a continuous need for the identification of more effective drug targets and the execution of mechanism of action (MOA) studies. Recently, epigenetic modifiers have been recognized as important therapeutic targets for hepatocellular carcinoma (HCC) based on their reported abilities to suppress HCC metastasis and proliferation in both in vivo and in vitro studies. Therefore, here, we introduce epigenetic modifiers and alterations related to HCC metastasis and proliferation, and their molecular mechanisms in HCC metastasis. The existing data suggest that the study of epigenetic modifiers is important for the development of specific inhibitors and diagnostic targets for HCC treatment.
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http://dx.doi.org/10.3390/ijms19123978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321007PMC
December 2018

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer.

Br J Cancer 2018 11 13;119(11):1347-1357. Epub 2018 Nov 13.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

Background: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation.

Methods: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library.

Results: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression.

Conclusions: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.
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http://dx.doi.org/10.1038/s41416-018-0289-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265273PMC
November 2018

o-Carboranylalkoxy-1,3,5-Triazine Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Activity.

Molecules 2018 Aug 30;23(9). Epub 2018 Aug 30.

Department of Chemistry, College of Natural Sciences, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju 61452, Korea.

Morpholine- and bis(2-methoxyethyl)amine-substituted 1,3,5-triazine derivatives containing an alkoxy-o-carborane in the 6-position of the triazine ring were successfully synthesized. The molecular structures of the methoxy- and ethoxy-o-carboranyl-1,3,5-triazines were established by X-ray crystallography. In vitro studies showed that the methylene bridged morpholine- and bis(2-methoxyethyl)amine-substituted o-carboranyl-1,3,5-triazines accumulated to high levels in B16 melanoma cells and exhibited higher cytotoxicity than p-boronophenylalanine.
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http://dx.doi.org/10.3390/molecules23092194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225125PMC
August 2018

DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells.

Oncogene 2018 03 15;37(9):1251-1262. Epub 2017 Dec 15.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) has an anti-apoptotic function during DNA damage in lung cancer. However, the anti-apoptotic mechanism of DDIAS in cancer cells under other conditions has not been reported. We report here that DDIAS protects cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by two distinct mechanisms in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) cells. DDIAS depletion sensitized NSCLC and HCC cells to TRAIL-mediated apoptosis, an effect that was abrogated by pharmacological or genetic inhibition of caspase-8 and was independent of caspase-9, p53, or mitogen-activated protein kinase signaling. Interestingly, we found that the N terminus of DDIAS interacted with the death effector domain of Fas-associated protein death domain (FADD) and prevented its recruitment to the death-inducing signaling complex (DISC), thereby blocking caspase-8 activation. DDIAS knockdown also suppressed epidermal growth factor-induced phosphorylation of p90 ribosomal S6 kinase (RSK) 2 and stabilized caspase-8 by preventing its ubiquitination and proteasomal degradation. This effect was abolished by RSK2 overexpression. Taken together, DDIAS has dual functions in inhibiting DISC formation as well as in destabilizing caspase-8, thereby suppressing TRAIL-mediated apoptosis of cancer cells. Thus, we suggest that DDIAS can serve as an effective therapeutic target in the treatment of NSCLC and HCC.
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http://dx.doi.org/10.1038/s41388-017-0025-yDOI Listing
March 2018

Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism.

J Med Chem 2017 10 16;60(20):8631-8646. Epub 2017 Oct 16.

College of Pharmacy, Dongguk University , Goyang 10326, Korea.

Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01231DOI Listing
October 2017

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

Cell Death Dis 2017 06 1;8(6):e2843. Epub 2017 Jun 1.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea.

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD, NADP, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.
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http://dx.doi.org/10.1038/cddis.2017.235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520894PMC
June 2017

Synthesis and biological evaluation of kresoxim-methyl analogues as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer cells.

Bioorg Med Chem Lett 2017 07 9;27(13):3026-3029. Epub 2017 May 9.

School of Chemistry and Biochemistry, Yeungnam University, 280 Daehak-Ro, Gyeongsan-si, Gyeongbuk 38541, Republic of Korea. Electronic address:

We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC values of 0.60-0.94µM. Under hypoxic condition, compounds 11b, 11c, and 11d increased the intracellular oxygen contents, thereby attenuating the hypoxia-induced accumulation of HIF-1α protein.
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http://dx.doi.org/10.1016/j.bmcl.2017.05.024DOI Listing
July 2017

Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells.

Bioorg Med Chem 2017 05 14;25(9):2601-2608. Epub 2017 Mar 14.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan. Electronic address:

Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.
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http://dx.doi.org/10.1016/j.bmc.2017.03.024DOI Listing
May 2017

Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells.

Cell Death Dis 2017 01 12;8(1):e2554. Epub 2017 Jan 12.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) rescues lung cancer cells from apoptosis in response to DNA damage. DDIAS is transcriptionally activated by NFATc1 and EGF-mediated ERK5/MEF2B, leading to cisplatin resistance and cell invasion. Therefore, DDIAS is suggested as a therapeutic target for lung cancer. Here, we report that DDIAS stability is regulated by E3 U-box ubiquitin ligase carboxyl terminus of HSP70-interacting protein (CHIP)-mediated proteasomal degradation. We first isolated CHIP as an interacting partner of DDIAS by yeast two-hybrid screening. CHIP physically associated with both the N- and C-terminal regions of DDIAS, targeting it for proteasomal degradation and reducing the DDIAS half-life. CHIP overexpression analyses indicated that the tetratrico peptide repeat (TPR) domain and the U-box are required for DDIAS ubiquitination. It is likely that HSP70-bound DDIAS is recruited to the CHIP E3 ligase via the TPR domain, suggesting DDIAS as a client protein of HSP70. In addition, CHIP overexpression in lung cancer cells expressing high DDIAS levels induced significant growth inhibition by enhancing DDIAS degradation. Furthermore, simultaneous CHIP overexpression and DNA damage agent treatment caused a substantial increase in the apoptosis of lung cancer cells. Taken together, these findings indicate that the stability of the DDIAS protein is regulated by CHIP/HSP70-mediated proteasomal degradation and that CHIP overexpression stimulates the apoptosis of lung cancer cells in response to DNA-damaging agents.
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http://dx.doi.org/10.1038/cddis.2016.488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386388PMC
January 2017

DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion.

Biochim Biophys Acta 2016 11 10;1859(11):1449-1458. Epub 2016 Jul 10.

Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Republic of Korea. Electronic address:

DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells. The genetic or pharmacological inhibition of ERK5 suppressed DDIAS induction following EGF exposure and the overexpression of constitutively active MEK5 (CA-MEK5) enhanced DDIAS expression. In chromatin immunoprecipitation assays, MEF2B, a downstream target of ERK5, exhibited sequence-specific binding to a MEF2 binding site in the DDIAS promoter following treatment with EGF. The overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas the knockdown of MEF2B impaired this effect. Furthermore, DDIAS promoted invasion by increasing β-catenin expression at the post-translational level in response to EGF, suggesting that DDIAS plays a crucial role in the metastasis of cancer cells by regulating β-catenin expression. It is unlikely that MEF2B and NFATc1 cooperatively regulate DDIAS transcription in response to EGF. Collectively, EGF activates the ERK5/MEF2 pathway, which in turn induces DDIAS expression to promote cancer cell invasion by activating β-catenin target genes.
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http://dx.doi.org/10.1016/j.bbagrm.2016.07.003DOI Listing
November 2016

Data on the transcriptional regulation of DNA damage induced apoptosis suppressor (DDIAS) by ERK5/MEF2B pathway in lung cancer cells.

Data Brief 2016 Dec 6;9:257-61. Epub 2016 Sep 6.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Korea.

The data included in this article are associated with the article entitled "DNA-damage-induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion" (J.Y. Im, S.H. Yoon, B.K. Kim, H.S. Ban, K.J. Won, K.S. Chung, K.E. Jung, M. Won) [1]. Quantitative RT-PCR data revealed that genetic or pharmacological inhibition of extracellular signal-regulated kinase 5 (ERK5) suppresses DDIAS transcription in response to epidermal growth factor (EGF) in Hela cells. p300 did not interact with myocyte enhancer factor 2B (MEF2B), a downstream target of ERK5 and affect transcription of DDIAS. Moreover, DDIAS transcription is activated by ERK5/MEF2B signaling on EGF exposure in the non-small cell lung cancer cells (NSCLC) NCI-H1703 and NCI-H1299. DDIAS knockdown suppresses lung cancer cell invasion by decreasing β-catenin protein level on EGF exposure.
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http://dx.doi.org/10.1016/j.dib.2016.08.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021921PMC
December 2016

A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration.

PLoS One 2016 9;11(9):e0162568. Epub 2016 Sep 9.

Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacetylamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structure-based virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1α and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1α accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017629PMC
August 2017

Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes.

Bioconjug Chem 2016 08 18;27(8):1911-20. Epub 2016 Jul 18.

College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.

We developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00305DOI Listing
August 2016

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).

Expert Opin Ther Pat 2016 16;26(3):309-22. Epub 2016 Feb 16.

d Chemical Resources Laboratory , Tokyo Institute of Technology , Yokohama , Japan.

Introduction: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported.

Areas Covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011-2015).

Expert Opinion: Although many of the HIF inhibitors reviewed in this patent survey possess inhibitory activity against cancer and HIF-related diseases, the compounds are still in the early stages of development, most likely due to the complexity of the HIF-1 pathway and their different mechanisms of action for HIF inhibition. Most cancer cells use the glycolytic pathway for energy production and HIF-1α participates deeply in the expression of several glycolytic enzymes. Therefore, a detailed study of HIF's function in cancer metabolisms may provide us an alternative strategy for further development of HIF inhibitors in cancer therapy.
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http://dx.doi.org/10.1517/13543776.2016.1146252DOI Listing
October 2016

NFATc1 regulates the transcription of DNA damage-induced apoptosis suppressor.

Data Brief 2015 Dec 17;5:975-80. Epub 2015 Nov 17.

Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.

DNA damage induced apoptosis suppressor (DDIAS), or human Noxin (hNoxin), is strongly expressed in lung cancers. DDIAS knockdown induced apoptosis in non-small cell lung carcinoma A549 cells in response to DNA damage, indicating DDIAS as a potential therapeutic target in lung cancer. To understand the transcriptional regulation of DDIAS, we determined the transcription start site, promoter region, and transcription factor. We found that DDIAS transcription begins at nucleotide 212 upstream of the DDIAS translation start site. We cloned the DDIAS promoter region and identified NFAT2 as a major transcription factor (Im et al., 2016 [1]). We demonstrated that NFATc1 regulates DDIAS expression in both pancreatic cancer Panc-1 cells and lung cancer cells.
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http://dx.doi.org/10.1016/j.dib.2015.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675896PMC
December 2015

Properties of a glycogen like polysaccharide produced by a mutant of Escherichia coli lacking glycogen synthase and maltodextrin phosphorylase.

Carbohydr Polym 2016 Jan 30;136:649-55. Epub 2015 Sep 30.

Department of Food Science and Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.

Escherichia coli mutant TBP38 lacks glycogen synthase (GlgA) and maltodextrin phosphorylase (MalP). When grown on maltose in fed-batch fermentation TBP38 accumulated more than 50-fold higher glycogen-type polysaccharide than its parental strain. The polysaccharides were extracted at different growth stages and migrated as one peak in size-exclusion chromatography. TBP38 produced polysaccharides ranging 2.6 × 10(6)-4.6 × 10(6)Da. A ratio of short side-chains (DP ≦ 12) in the polysaccharides was greater than 50%, and number-average degree of polymerization varied from 9.8 to 8.4. The polysaccharides showed 70-290 times greater water-solubility than amylopectin. Km values using porcine and human pancreatic α-amylases with polysaccharides were 2- to 4-fold larger than that of amylopectin. kcat values were similar for both α-amylases. The TBP38 polysaccharides had 40-60% lower digestibility to amyloglucosidase than amylopectin. Intriguingly, the polysaccharides showed strong immunostimulating effects on mouse macrophage cell comparable to lipopolysaccharides. The lipopolysaccharide contamination levels were too low to account for this effect.
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http://dx.doi.org/10.1016/j.carbpol.2015.09.091DOI Listing
January 2016

DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.

Biochim Biophys Acta 2016 Jan 25;1863(1):40-9. Epub 2015 Oct 25.

Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address:

In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer-specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells.
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http://dx.doi.org/10.1016/j.bbamcr.2015.10.011DOI Listing
January 2016

Boron-Based Drug Design.

Chem Rec 2015 Jun 20;15(3):616-35. Epub 2015 Mar 20.

Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan.

The use of the element boron, which is not generally observed in a living body, possesses a high potential for the discovery of new biological activity in pharmaceutical drug design. In this account, we describe our recent developments in boron-based drug design, including boronic acid containing protein tyrosine kinase inhibitors, proteasome inhibitors, and tubulin polymerization inhibitors, and ortho-carborane-containing proteasome activators, hypoxia-inducible factor 1 inhibitors, and topoisomerase inhibitors. Furthermore, we applied a closo-dodecaborate as a water-soluble moiety as well as a boron-10 source for the design of boron carriers in boron neutron capture therapy, such as boronated porphyrins and boron lipids for a liposomal boron delivery system.
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http://dx.doi.org/10.1002/tcr.201402100DOI Listing
June 2015

Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors.

J Med Chem 2014 Nov 12;57(22):9522-38. Epub 2014 Nov 12.

BK21Plus R-FIND Team, College of Pharmacy, Dongguk University-Seoul , Koyang, 410-820, Korea.

A structure-activity relationship study of hypoxia inducible factor-1α inhibitor 3-aminobenzoic acid-based chemical probes, which were previously identified to bind to mitochondrial malate dehydrogenase 2, was performed to provide a better understanding of the pharmacological effects of LW6 and its relation to hypoxia inducible factor-1α (HIF-1α) and malate dehydrogenase 2 (MDH2). A variety of multifunctional probes including the benzophenone or the trifluoromethyl diazirine for photoaffinity labeling and click reaction were prepared and evaluated for their biological activity using a cell-based HRE-luciferase assay as well as a MDH2 assay in human colorectal cancer HCT116 cells. Among them, the diazirine probe 4a showed strong inhibitory activity against both HIF-1α and MDH2. Significantly, the inhibitory effect of the probes on HIF-1α activity was consistent with that of the MDH2 enzyme assay, which was further confirmed by the effect on in vitro binding activity to recombinant human MDH2, oxygen consumption, ATP production, and AMP activated protein kinase (AMPK) activation. Competitive binding modes of LW6 and probe 4a to MDH2 were also demonstrated.
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http://dx.doi.org/10.1021/jm501241gDOI Listing
November 2014

p300 cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription in NSC126188-mediated apoptosis.

Biochim Biophys Acta 2014 May 15;1839(5):364-73. Epub 2014 Mar 15.

BioMedical Genomics Research Center, KRIBB, Daejeon 305-806, Korea; Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea. Electronic address:

The anti-cancer agent NSC126188 induces apoptosis of stomach carcinoma NUGC-3 cells by inducing RhoB expression. Here, we present that the p300 binding site in the RhoB promoter is crucial for the binding of p300 and its partner transcription factors to activate RhoB transcription in NSC126188-mediated apoptosis. NSC126188 increased expression of p300 and c-Jun. Conversely, knockdown of p300 decreased RhoB expression in the presence of NSC126188. We found that poly(ADP-ribose) polymerase-1 (PARP-1) was associated with the p300 binding site and that PARP-1 knockdown inhibited NSC126188-mediated RhoB expression. In the cells treated with NSC126188, p300, PARP-1, and c-Jun interacted and bound the p300 binding site. Furthermore, chromatin immunoprecipitation (ChIP) analysis revealed strong p300 binding and weak c-Jun binding at the p300 binding site of RhoB promoter in cells treated with NSC126188. We also demonstrated that c-Jun played a crucial role in p300 binding. However, PARP-1 did not directly bind the p300 binding site, suggesting a bridging role between p300 and c-Jun. Electrophoretic mobility shift assays demonstrated a complex comprising p300/c-Jun/PARP-1 that bound wild type, but not a mutated, p300 binding site. In addition, overexpression of p300, PARP-1, or c-Jun dramatically enhanced RhoB promoter activity when it contained the wild type sequence but not mutated sequences, indicating the crucial role of the p300 binding site in NSC126188-induced transcription of RhoB. Taken together, these data suggest that p300 is recruited and cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription during NSC126188-mediated apoptosis.
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http://dx.doi.org/10.1016/j.bbagrm.2014.03.004DOI Listing
May 2014