Key Spec Table
|Species Reactivity||Key Applications||Host||Format||Antibody Type|
|T, H||ICC, IP, WB, ChIP||Rb||Purified||Polyclonal Antibody|
|Safety Information according to GHS|
|Material Size||200 µg|
|Anti-acetyl-Histone H4 - 2387828||2387828|
|Anti-acetyl-Histone H4 - 2424765||2424765|
|Anti-acetyl-Histone H4 - 15793||15793|
|Anti-acetyl-Histone H4 - 16728||16728|
|Anti-acetyl-Histone H4 - 17942||17942|
|Anti-acetyl-Histone H4 - 19602||19602|
|Anti-acetyl-Histone H4 - 2019720||2019720|
|Anti-acetyl-Histone H4 - 2302181||2302181|
|Anti-acetyl-Histone H4 - 23224||23224|
|Reference overview||Application||Species||Pub Med ID|
|Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor.|
Kim, GH; Oh, GS; Yoon, J; Lee, GG; Lee, KU; Kim, SW
The Journal of clinical investigation 125 183-93 2015
Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.
|Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.|
Wang, G; Niu, X; Zhang, W; Caldwell, JT; Edwards, H; Chen, W; Taub, JW; Zhao, L; Ge, Y
Cancer letters 356 656-68 2015
Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease.
|Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area.|
Koo, JW; Mazei-Robison, MS; LaPlant, Q; Egervari, G; Braunscheidel, KM; Adank, DN; Ferguson, D; Feng, J; Sun, H; Scobie, KN; Damez-Werno, DM; Ribeiro, E; Peña, CJ; Walker, D; Bagot, RC; Cahill, ME; Anderson, SA; Labonté, B; Hodes, GE; Browne, H; Chadwick, B; Robison, AJ; Vialou, VF; Dias, C; Lorsch, Z; Mouzon, E; Lobo, MK; Dietz, DM; Russo, SJ; Neve, RL; Hurd, YL; Nestler, EJ
Nature neuroscience 18 415-22 2015
Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.
|ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat.|
Meidhof, S; Brabletz, S; Lehmann, W; Preca, BT; Mock, K; Ruh, M; Schüler, J; Berthold, M; Weber, A; Burk, U; Lübbert, M; Puhr, M; Culig, Z; Wellner, U; Keck, T; Bronsert, P; Küsters, S; Hopt, UT; Stemmler, MP; Brabletz, T
EMBO molecular medicine 7 831-47 2015
Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial-mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.
|Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.|
Lu, H; Xue, Y; Xue, Y; Yu, GK; Arias, C; Lin, J; Fong, S; Faure, M; Weisburd, B; Ji, X; Mercier, A; Sutton, J; Luo, K; Gao, Z; Zhou, Q
eLife 4 e06535 2015
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.
|Berberine reverses abnormal expression of L-type pyruvate kinase by DNA demethylation and histone acetylation in the livers of the non-alcoholic fatty disease rat.|
Zhang, Y; Chang, X; Song, X; Chen, C; Chen, H; Lu, Z; Gao, X; Lu, D
Int J Clin Exp Med 8 7535-43 2015
Berberine (BBR) can potentially be used as a drug against non-alcoholic fatty liver disease (NAFLD) and diabetes. Our previous study found that BBR could change the pattern of DNA methylation. But the mechanisms underlying berberine are still far from completely understood. In this study, the function of L-PK in cell metabolism was explored, and high-fat-diet induced SD rats NAFLD models were created. The NAFLD rats were randomly grouped to be oral administration with BBR at a dosage of 200 mg/kg daily. Then DNA methylation and histone acetylation around the L-type Pyruvate Kinase (L-PK) gene were examined. In the results, we found that L-PK had a positive effect on cell proliferation, glucose utilization and triglyceride metabolism. However, the expression of L-PK was reduced in the livers of NAFLD rats, in accord with the decrease of DNA hypermethylation and histone deacetylation in the regulatory regions of L-PK. Notably, BBR treatment can restore the expression of L-PK by the demethylation of L-PK promoter and the increase in acetylation levels of histone H3 and H4 around L-PK, which indicated that BBR may be a potential drug for epigenetic-included diseases.
|5-Hydroxymethylcytosine Plays a Critical Role in Glioblastomagenesis by Recruiting the CHTOP-Methylosome Complex.|
Takai, H; Masuda, K; Sato, T; Sakaguchi, Y; Suzuki, T; Suzuki, T; Koyama-Nasu, R; Nasu-Nishimura, Y; Katou, Y; Ogawa, H; Morishita, Y; Kozuka-Hata, H; Oyama, M; Todo, T; Ino, Y; Mukasa, A; Saito, N; Toyoshima, C; Shirahige, K; Akiyama, T
Cell reports 9 48-60 2014
The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes.
|Histone deacetylase inhibition with valproic acid downregulates osteocalcin gene expression in human dental pulp stem cells and osteoblasts: evidence for HDAC2 involvement.|
Paino, F; La Noce, M; Tirino, V; Naddeo, P; Desiderio, V; Pirozzi, G; De Rosa, A; Laino, L; Altucci, L; Papaccio, G
Stem cells (Dayton, Ohio) 32 279-89 2014
Adult mesenchymal stem cells, such as dental pulp stem cells, are of great interest for cell-based tissue engineering strategies because they can differentiate into a variety of tissue-specific cells, above all, into osteoblasts. In recent years, epigenetic studies on stem cells have indicated that specific histone alterations and modifying enzymes play essential roles in cell differentiation. However, although several studies have reported that valproic acid (VPA)-a selective inhibitor of histone deacetylases (HDAC)-enhances osteoblast differentiation, data on osteocalcin expression-a late-stage marker of differentiation-are limited. We therefore decided to study the effect of VPA on dental pulp stem cell differentiation. A low concentration of VPA did not reduce cell viability, proliferation, or cell cycle profile. However, it was sufficient to significantly enhance matrix mineralization by increasing osteopontin and bone sialoprotein expression. In contrast, osteocalcin levels were decreased, an effect induced at the transcriptional level, and were strongly correlated with inhibition of HDAC2. In fact, HDAC2 silencing with shRNA produced a similar effect to that of VPA treatment on the expression of osteoblast-related markers. We conclude that VPA does not induce terminal differentiation of osteoblasts, but stimulates the generation of less mature cells. Moreover, specific suppression of an individual HDAC by RNA interference could enhance only a single aspect of osteoblast differentiation, and thus produce selective effects.
|Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans.|
Lee, CC; Tsai, YT; Kao, CW; Lee, LW; Lai, HJ; Ma, TH; Chang, YS; Yeh, NH; Lo, SJ
Cell death & disease 5 e1158 2014
Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in the early embryo. Here, we established a C. elegans model for studying Nopp140-associated ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4 (H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C. elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5 mutant of C. elegans can be a valuable model for studying human Nopp140-associated ribosomopathy at the cellular and molecular levels.
|Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells.|
Pickholtz, I; Saadyan, S; Keshet, GI; Wang, VS; Cohen, R; Bouwman, P; Jonkers, J; Byers, SW; Papa, MZ; Yarden, RI
Oncotarget 5 11827-46 2014
Carriers of germline mutations in the BRCA1 gene have a significant increased lifetime risk for being diagnosed with breast cancer. The incomplete penetrance of BRCA1 suggests that environmental and/or genetic factors modify the risk and incidence among mutation carriers. Nutrition and particular micronutrients play a central role in modifying the phenotypic expression of a given genotype by regulating chromatin structure and gene expression. The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is a potent inhibitor of breast cancer growth. Here we report that two non-calcemic analogues of 1α,25-dihydroxyvitamin D3, seocalcitol (EB1089) and QW-1624F2-2, collaborate with BRCA1 in mediating growth inhibition of breast cancer cells and breast cancer stem-like cells. EB1089 induces a G1/S phase growth arrest that coincides with induction of p21waf1 expression only in BRCA1-expressing cells. A complete knockdown of BRCA1 or p21waf1 renders the cells unresponsive to EB1089. Furthermore, we show that in the presence of ligand, BRCA1 associates with vitamin D receptor (VDR) and the complex co-occupies vitamin D responsive elements (VDRE) at the CDKN1A (p21waf1) promoter and enhances acetylation of histone H3 and H4 at these sites. Thus, BRCA1 expression is critical for mediating the biological impact of vitamin D3 in breast tumor cells.