Abstract
BackgroundAlternative splicing is a ubiquitous post-transcriptional regulation mechanism in most eukaryotic genes. Aberrant splicing isoforms and abnormal isoform ratios can contribute to cancer development. Kinase genes are key regulators of multiple cellular processes. Many kinases are found to be oncogenic and have been intensively investigated in the study of cancer and drugs. RNA-Seq provides a powerful technology for genome-wide study of alternative splicing in cancer besides the conventional gene expression profiling. But this potential has not been fully demonstrated yet.MethodsWe characterized the transcriptome profile of prostate cancer using RNA-Seq data from viewpoints of both differential expression and differential splicing, with an emphasis on kinase genes and their splicing variations. We built a pipeline to conduct differential expression and differential splicing analysis, followed by functional enrichment analysis. We performed kinase domain analysis to identify the functionally important candidate kinase gene in prostate cancer, and calculated the expression levels of isoforms to explore the function of isoform switching of kinase genes in prostate cancer.ResultsWe identified distinct gene groups from differential expression and splicing analyses, which suggested that alternative splicing adds another level to gene expression regulation. Enriched GO terms of differentially expressed and spliced kinase genes were found to play different roles in regulation of cellular metabolism. Function analysis on differentially spliced kinase genes showed that differentially spliced exons of these genes are significantly enriched in protein kinase domains. Among them, we found that gene CDK5 has isoform switching between prostate cancer and benign tissues, which may affect cancer development by changing androgen receptor (AR) phosphorylation. The observation was validated in another RNA-Seq dataset of prostate cancer cell lines.ConclusionsOur work characterized the expression and splicing profiles of kinase genes in prostate cancer and proposed a hypothetical model on isoform switching of CDK5 and AR phosphorylation in prostate cancer. These findings bring new understanding to the role of alternatively spliced kinases in prostate cancer and also demonstrate the use of RNA-Seq data in studying alternative splicing in cancer.
Highlights
Alternative splicing is a ubiquitous post-transcriptional regulation mechanism in most eukaryotic genes
The expression of PLA2G2A has been reported significantly increased in prostate cancer comparing to benign tissue, and it might serve as a prognostic maker for prostate cancer [21]
In summary, our study provided a transcriptome profile of prostate cancer using RNA-Seq data with an emphasis on differentially spliced kinase genes
Summary
Alternative splicing is a ubiquitous post-transcriptional regulation mechanism in most eukaryotic genes. RNA-Seq provides a powerful technology for genome-wide study of alternative splicing in cancer besides the conventional gene expression profiling. This potential has not been fully demonstrated yet. Alternative splicing is an important post-transcriptional regulation mechanism through which one gene can produce multiple isoforms. It is ubiquitous in human cells, and about 95% of human multi-exon genes undergo this process [1]. RNA-Seq technology and bioinformatics methods have provided great opportunities for studying alternative splicing in cancers [4]
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