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Gene Expression Profiling Induced by Histone Deacetylase Inhibitor, FK228, in Human Esophageal Squamous Cancer Cells

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Gene Expression Profiling Induced by Histone Deacetylase Inhibitor, FK228, in Human Esophageal Squamous Cancer Cells 585-592 25/7/07 16:27 Page 585 ONCOLOGY REPORTS 18: 585-592, 2007 585 Gene expression profiling induced by histone deacetylase inhibitor, FK228, in human esophageal squamous cancer cells ISAMU HOSHINO, HISAHIRO MATSUBARA, YASUNORI AKUTSU, TAKANORI NISHIMORI, YASUO YONEYAMA, KENTARO MURAKAMI, AKI KOMATSU, HARUHITO SAKATA, KAZUYUKI MATSUSHITA and TAKENORI OCHIAI Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan Received March 31, 2007; Accepted May 29, 2007 Abstract. Histone deacetylase inhibitors (HDACIs) are optimal chemotherapy agents for ESCC (3). However, the promising therapeutic agents with the potential for regulating response rates of these combination chemotherapies are not cell cycle, differentiation and apoptosis in cancer cells. satisfactory and the development of new anticancer drugs is HDACI activity is associated with selective transcriptional expected to improve the prognosis of ESCC. Histone regulation and altering gene expression. However, the exact deacetylase inhibitors (HDACIs) are considered to represent mechanisms leading to the antitumor effect of HDACIs are one of the most promising agents for this purpose. not fully understood. FK228, one of the powerful HDACIs, The balance of acetylation by histone acetylases and strongly inhibited cell growth of T.Tn and TE2 cells and deacetylation by histone deacetylase prevents full acetylation, induced apoptosis. Therefore, comprehensive analysis of the thereby creating a default underacetylated state. Acetylated changes in gene expression in human esophageal cancer cell histone tails and other chromosome-associated proteins have lines by the HDACI FK228 was carried out by microarray been identified in nucleosomes and shown to be important in analysis. This analysis was used to clarify the expression regulating gene expression (4,5). Histone acetylation is often profiles of genes after exposure to FK228. Of the 4,608 genes associated with the transcription of gene characteristics of the analyzed, 93 genes in T.Tn and 65 genes in TE2 were up- or differentiated state. In contrast, histone deacetylation correlates down-regulated 2-fold or more at least at one time point during with transcriptional silencing and specifically, down-regulation FK228 exposure and they were classified into four clusters of the expression of pro-apoptotic genes. The anticancer based on their expression patterns. Among them, 15 genes effects of HDACIs were mainly thought to be activated by were contained in both cell lines and their expression patterns the modulation of gene expression patterns including genes were similar. Except p21, Prdx1 (reported by us) and associated with cell cycle arrest and apoptosis by inhibiting IGFBP3, the behaviour/expression of 12 highly responsive HDAC activities. The induction of apoptosis by HDACIs via genes has still not been reported in esophageal cancer cells. cell death pathways mediated by TRAIL, Fas, Bid and p53 These observations of the expression patterns of functionally was also reported (6-10). However, a comprehensive analysis classified genes provided insights into the mechanism of the of the expression profiles of these genes has not been antitumor effect of FK228 in esophageal squamous reported. carcinoma. FK228, one of the novel histone deacetylase inhibitors and isolated from chromobacterium violaceum, has exhibited Introduction remarkable antitumor activity in xenograft models and patients with cutaneous T-cell lymphoma had a complete or Esophageal squamous cell carcinoma (ESCC) remains one of partial response in a phase I trial (11,12). The current study the intractable cancers due to its higher incidence in older was designed to explore the efficacy of the antitumor activity patients and its rapid infiltration into neighboring tissues on human esophageal squamous cancer cell lines and to despite the recent progress in multi-modal approaches (1,2). identify and characterize additional target genes of FK228. By Currently, cisplatin and 5-fluorouracil are considered the using microarray analysis, we revealed gene expression profiles during the exposure of FK228 for up to 48 h. Ninety- three genes in T.Tn and 65 genes in TE2 were shown to be _________________________________________ regulated during the course of FK228 exposure. Among them, 15 genes showed substantial induction in both cell lines and Correspondence to: Hisahiro Matsubara, Department of Frontier their microarray analysis gave insights into the roles and Surgery, Graduate School of Medicine, Chiba University, Inohana regulation of genes by FK228. 1-8-1, Chuo-ku, Chiba 260-8670, Japan E-mail: [email protected] Materials and methods Key words: histone deacetylase inhibitor, FK228, esophageal Assay of cytotoxicity. Cell growth was determined by Cell squamous cell carcinoma Counting Kit-8 (Dojindo, Kumamoto, Japan). 5x103 cells per well were seeded into 96-well microplates and incubated for 585-592 25/7/07 16:27 Page 586 586 HOSHINO et al: GENE EXPRESSION PROFILING BY HDACI IN ESOPHAGEAL SCC 48 h at 37˚C under 5% CO2. FK228 was dissolved in ethanol and diluted with DMEM. After changing the medium, test samples were changed and incubated in the presence or absence of drugs for 72 h. Then the Cell Counting Kit-8 reagent was added and allowed to react for 3 h. Absorbance at 450 nm was measured using a microplate reader (Bio-Rad Laboratories, Hercules, CA). The IC50 (50% inhibitory concentration) values were calculated by the least squares method. mRNA preparation and cDNA microarray analysis. Cells were seeded into 225-cm2 flasks and incubated for 48 h, then treated with or without IC80 concentration of FK228 for up to 48 h and harvested at 0, 6, 12, 24 and 48 h. Cells were washed with PBS and processed for RNA extraction with the RNeasy Kit Figure 1. Effect of FK228 on human esophageal squamous cancer cell lines, (Qiagen Inc., Chatsworth, CA) according to the manufacturer's TE2 and T.Tn. Cells were incubated for 72 h in the absence or presence of the instructions. Total RNA (20 μg) from cells cultured with indicated concentrations of FK228. Then, the growth inhibitory effect of FK228 was compared with 20 μg of total RNA from cells FK228 was examined by Cell Counting Kit-8 as described in Materials and methods. Data are presented as a percentage of viability in control ± SD cultured without FK228, using the cDNA microarray, which (n=8). consisted of 4608 distinct cDNA clones, generated as described previously (13). Fluorescent images of the hybridized microarrays were scanned with a fluorescence laser confocal slide scanner (Scan Array 4000, GSI Lumonics, and 5'-GAAGCATGTCCCTCTTGTCTTG-3'; GAPDH: 5'- Nepean, Canada) and analyzed with Quant Array software ACCACAGTCCATGCCATCAC-3' and 5'-TCCACCACCC (GSI Lumonics, Nepean, Canada) according to the TGTTGCTGTA-3'. The expression value was calculated as manufacturer's instructions. All experiments were done in follows: expression level of each mRNA/expression level of duplicate and averaged data for each of the time points were GAPDH. subjected to statistical analysis. To identify genes significantly expressed, we defined the data for those genes that showed Annotation of gene function. The normalized Cy5/Cy3 ratios in 2-fold changes for at least one time point. the microarray analysis were log2-transformed and used to classify the patterns of serial changes of the gene expression. Real-time quantitative RT-PCR. The expression changes of 5 Genes whose expression levels varied at least 2-fold at any of randomly selected genes (prohibitin, S100A6, ZNF24, the time points were subjected to a hierarchical clustering EIF4A1, cyclin I) were also examined by real-time analysis using the algorithm of Euclid and Ward in Gene- quantitative PCR using the Light Cycler technique (Roche Maths software (Applied Maths BVBA, Sint-Martens-Latem, Diagnostics GmbH, Mannheim, Germany). The cDNA Belgium). templates for real-time PCR were synthesized from 1 μg of The molecular functions of the genes were assigned by total RNA using SuperScript II reverse transcriptase and an referring to Gene Ontology™ (www.geneontology.org/) and oligo-dT primer. The glyceraldehyde-3-phosphate dehydro- GeneCards™ (bioinfo.weizmann.ac.il/cards/). genase (GAPDH) gene served as an internal control. The PCR reaction consisted of DNA Master SYBR-Green I mix Results (Light Cycler-FastStart DNA Master SYBR-Green I kit, Roche Diagnostics; containing Taq DNA polymerase, dNTP, FK228 demonstrated anti-proliferative activity by inducing 3 mM MgCl2 and SYBR-Green dye), 0.5 μM each primer apoptosis in human esophageal cancer cell lines. FK228 has and cDNA. The PCR processes were as follows: initial apparent anti-proliferative activity against human cancer denaturation at 95˚C for 10 min, followed by 45 cycles of cells (6-10,14). First, the effect of FK228 on cell growth was denaturation at 95˚C for 15 sec, annealing at 57˚C for 10 sec determined in the human esophageal cancer T.Tn and TE2 and elongation at 72˚C for 8-18 sec. The Fit Points method cells. A lower dose (IC50 values were 0.373 and 0.781 provided by the Light Cycler software was used to estimate the ng/ml, respectively) of FK228 produced changes in growth concentration of each sample. Primers were chosen using rate compared to control cells at 72 h in both T.Tn and TE2 Primer 3 (available at: http://www-genome.wi.mit.edu/cgi- cell lines (Fig. 1). In addition, our previous data (14) showed bin/primer/primer3_www.cgi). The following primer that FK228 significantly induced apoptosis.
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