Systematic analysis of time-series gene expression data on tumor cell-selective apoptotic responses to HDAC inhibitors.

Yunfeng Qi ,Yan Dong,Yin Wu,Yongli Bao ,Yanxin Huang ,Luguo Sun ,Chunlei Yu ,Lihua Zheng ,Hongyu Jiang ,Yuxin Li

doi:10.1155/2014/867289

Abstract

SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.

Highlights

Histone acetylation is controlled by histone acetyltransferases (HATs), while histone deacetylases (HDACs) counterbalance activity of HATs [1]
Our analyses indicated that SAHA selectively disrupted the DNA damage response (DDR), cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis
Genes in a pathway are believed to be regulated in a more coordinated fashion than a random pathway; expression patterns of these genes are expected to be coherent. To test whether this hypothesis was appropriate for SAHAtreated tumor and normal samples, we computed H-score values for all defined pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG), BioCarta, and gene ontology (GO)

Summary

Introduction

Histone acetylation is controlled by histone acetyltransferases (HATs), while histone deacetylases (HDACs) counterbalance activity of HATs [1]. Similar to results described above, true pathways were found to be significantly more coherent than random gene sets at all time points (0 h, 4 h, 12 h, and 24 h) for both tumor and normal samples (Table 2). The DNA repair, cell cycle, p53, and mitochondrial respiratory chain pathways all showed a coherence change between tumor and normal samples at some time points.

Results

Conclusion