Unknown,Transcriptomics,Genomics,Proteomics

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A Multi-loop, Double-cube Microarray Design Applied to Prostate Cancer Cell Lines with Variable Sensitivity to Histone Deacetylase Inhibitors

ABSTRACT: Implementation of a complex design for a microarray experiment on resistance mechanisms of histone deacetylase inhibitors (HDACI). To improve our understanding of the underlying mechanism of HDACI resistance in prostate cancer cells, we designed a novel ‘‘multiple-loop, double-cube’’ cDNA microarray experiment. In the experiment DU-145 and PC3 cells were treated with two different HDACIs (vorinostat and valproic acid) and incubation periods (48 and 96 hours). Preprocessing included exploratory analyses of the quality of the arrays and intensity-dependent within-array Loess normalization. An ANOVA model was used for inference. The results were validated by Western blot analysis of known treatment targets.

ORGANISM(S): Homo sapiens

SUBMITTER: Luigi Marchionni

PROVIDER: E-GEOD-34452 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable sensitivity to histone deacetylase inhibitors.

Kortenhorst Madeleine S Q MS Zahurak Marianna M Shabbeer Shabana S Kachhap Sushant S Galloway Nathan N Parmigiani Giovanni G Verheul Henk M W HM Carducci Michael A MA

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 21

<h4>Purpose</h4>Although microarray technology has been widely adopted by the scientific community, analysis of the ensuing data remains challenging. In this article, we present our experience with a complex design microarray experiment on resistance mechanisms of histone deacetylase inhibitors (HDACI).<h4>Experimental design</h4>To improve our understanding of the underlying mechanism of HDACI resistance in prostate cancer cells, we designed a novel "multiple-loop, double-cube" cDNA microarray ...[more]

PMID: 18980983

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Project description:Studying chemical disturbances during neural differentiation of mES cells has been established as an alternative in vitro testing approach for the identification of developmental toxicants. miRNAs represent a class of small regulatory RNA molecules, which bind to target mRNAs thereby repressing their translation. Many studies have shown an essential role of miRNAs in regulation of gene expression during development and ESC differentiation. Thus, neural differentiation of ESC in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed the expression of miRNAs and transcriptomics changes during neural differentiation of mESC exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neural differentiating mES cells under VPA treatment (300ÂµM) compared to solvent control on day 16 of differentiation. Analysis of miRNA expression revealed that valproate switches the lineage specification from neural to myogenic differentiation (upregulation of muscle-enriched miRNAs mir-206, mir-133a and mir-10a and downregulation of neuro-specific miRNAs mir-124a, mir-128 and mir-137). The findings on the miRNA level could be confirmed on mRNA level (induction of expression of myogenic regulatory factors (MRFs) as well as muscle specific genes (Actc1, calponin, myosin light chain, asporin, decorin) and repression of genes involved in neurogenesis (Otx1 and 2, Zic3, 4, 5)) as well as morphologically by immunocytochemistry. The observed results were VPA specific and most probably due to inhibition of histone deacetylase (HDAC) activity of VPA for two reasons: (i) we did not observe any induction of muscle specific miRNAs in neural differentiating ES cells exposed to the unrelated developmental neurotoxicant sodium arsenite; (ii) expression of muscle specific mir-206 and muscle enriched mir-10a was similarly increased in cells exposed to a structurally different HDAC inhibitor, trichostatin A (TSA). Furthermore, using our in vitro cell system we could confirm an aberrant expression of known VPA target genes and genes involved in neural tube closure. We conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. Observed lineage shift into myogenesis, where miRNAs play a significant role, could be a major developmental neurotoxical mechanism of VPA. We used microarray approach to identify altered miRNA expression in neural differentiated mES cells exposed to two known developmental neurotxicants and epigenetic active substances, sodium valproate (VPA) and sodium arsenite (As) mES cells line W4 were induced to differnetiate to neurons under exposure to VPA and As for 16 days. RNA for microarrays was collected on day 16 of differentiation from three biological replicates of solvent controls (PBS was used as a solvent for VPA and H20 for As) or substance treated cells.

Dataset Information

A Multi-loop, Double-cube Microarray Design Applied to Prostate Cancer Cell Lines with Variable Sensitivity to Histone Deacetylase Inhibitors

Publications

A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable sensitivity to histone deacetylase inhibitors.

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