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H3K9K14ac ChIP-chip in lung cancer cells treated with histone deacetylase inhibitor

ABSTRACT: Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, mitosis and cytokinesis were inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. Chromatin-immunoprecipitation-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. Collectively, our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20304 | GEO | 2010/12/22

SECONDARY ACCESSION(S): PRJNA125343

REPOSITORIES: GEO

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H3K9K14ac ChIP-chip in lung cancer cells treated with histone deacetylase inhibitor

Project description:Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, mitosis and cytokinesis were inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. Chromatin-immunoprecipitation-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. Collectively, our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy. ChIP-chip analysis for H3K9K14ac in A549, H1299 and CL1-1 lung cancer cells treated with 2.5 uM histone deacetylase inhibitor, OSU-HDAC-44, for 2 hours.

2010-12-22 | E-GEOD-20304 | biostudies-arrayexpress

Transcription profiling of human

Project description:This SuperSeries is composed of the following subset Series:; GSE9974: The effect of the HDAC inhibitor OSU-HDAC42 on gene expression in esophageal tissues and adenocarcinoma cells I; GSE9976: The effect of the HDAC inhibitor OSU-HDAC42 on gene expression in esophageal tissues and adenocarcinoma cells II Experiment Overall Design: Refer to individual Series

2008-04-05 | E-GEOD-9987 | biostudies-arrayexpress

The effect of the HDAC inhibitor OSU-HDAC42 on gene expression in esophageal tissues and adenocarcinoma cells I

Project description:Title: In vitro and in vivo effects of the orally bioavailable phenylbutyrate-derived histone deacetylase inhibitor OSU-HDAC42 on gene expression in esophageal tissues and in esophageal adenocarcinoma cells Histone deacetylases (HDACs) modulate nucleosomal packaging of DNA, thereby influencing gene transcription and multiple cancer-associated processes. Thus, we conducted microarray analysis at multiple time-points to assess the ability of OSU-HDAC42, the S enantiomer of the previously published compound HDAC-42, to modulate key acid-induced changes as well as to impact other genes altered as the normal esophageal epithelium progresses along the metaplasia-dysplasia-esophageal adenocarcinoma continuum. Keywords: acid-pulsed cells pretreated with OSU-HDAC42 or vehicle

2008-03-20 | GSE9974 | GEO

Transcription profiling of human SEG1 esophageal cell line treated with OSU-HDAC42, time series

Project description:Title: In vitro and in vivo effects of the orally bioavailable phenylbutyrate-derived histone deacetylase inhibitor OSU-HDAC42 on gene expression in esophageal tissues and in esophageal adenocarcinoma cells; Histone deacetylases (HDACs) modulate nucleosomal packaging of DNA, thereby influencing gene transcription and multiple cancer-associated processes. Thus, we conducted microarray analysis at multiple time-points to assess the ability of OSU-HDAC42, the S enantiomer of the previously published compound HDAC-42, to modulate key acid-induced changes as well as to impact other genes altered as the normal esophageal epithelium progresses along the metaplasia-dysplasia-esophageal adenocarcinoma continuum. Experiment Overall Design: SEG-1 cells were pretreated for 24 hours with vehicle or OSU-HDAC42, pulsed with acidified media (pH 3.5; 20 mins at 37C), replenished with media or OSU-HDAC42, and harvested 3, 6 and 24 hours later. Global gene expression analysis was conducted using the human genome chip U133 2.0 Plus.

2008-04-05 | E-GEOD-9974 | biostudies-arrayexpress

Hydroxychloroquine + Vorinostat in Advanced Solid Tumors

Project description:This study is an open label non randomized study of hydroxychloroquine (HCQ) with histone deacetylase (HDAC) inhibitor Vorinostat in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and to evaluate the safety and antitumor activity of this drug combination.

| 2081555 | ecrin-mdr-crc

Combining Sodium Valproate With Standard-of-care EGFR (Epidermal Growth Factor Receptor) Monoclonal Antibody Treatment in Patients With Metastatic Colorectal Cancer

Project description:The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC.

| 5791 | ecrin-mdr-crc

The effect of the HDAC inhibitor OSU-HDAC42 on gene expression in esophageal tissues and adenocarcinoma cells II

2008-03-20 | GSE9976 | GEO

Molecular changes in cancer cells exposed to an HDAC inhibitor: A metabolomics approach

Project description:Histone deacetylase (HDAC) inhibitors are part of a new generation of epigenetic drugs for cancer treatment. It is known that histone acetylation plays a key role in controlling essential chromosome functions, including gene regulation, and this process has been linked with cancer development and progression. Better understanding of molecular mechanisms involving HDAC inhibitors is needed for the design of new targeted drugs, and also to evaluate the effectiveness of current treatments. In this study, an untargeted metabolomics approach was used to identify intracellular metabolite deregulation after treating cancer cell lines with the HDAC inhibitor HC-Toxin. Metabolomics analysis was performed using high resolution mass spectrometry, in combination with univariate and multivariate statistics and pathway analysis. HDAC inhibition showed highly specific metabolic changes in cancer cell lines compared to non-cancerous cells. In particular, N-acetyl-L-cysteine, N-acetylmethionine, and N-acetyl-L-carnitine showed a dose dependent change. Moreover, pathways controlling protein biosynthesis, as well as tryptophan, cysteine and methionine metabolism were significantly altered by HDAC inhibition. This study illustrates that HDAC inhibition has multiple effects on different metabolic pathways and our results can be extrapolated to inform on the molecular transitions in human cells.

2022-05-04 | MTBLS682 | MetaboLights

MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

Project description:MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function. BE(2)-C neuroblastoma cells were treated with the pan-HDACi HC-toxin (20 nM) or solvent control (methanol) for 24 h in three replicates, respectively.Total RNA was isolated using miRNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. RNA was eluted in water. The quality of total RNA was checked by gel analysis using the total RNA Nanochip assay on an Agilent 2100 Bioanalyzer.

2013-05-01 | E-GEOD-44538 | biostudies-arrayexpress

MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

2013-05-01 | GSE44538 | GEO

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