Abstract
Background: Androgen steroid hormones are key drivers of prostate cancer. Previous work has shown that androgens can drive the expression of alternative mRNA isoforms as well as transcriptional changes in prostate cancer cells. Yet to what extent androgens control alternative mRNA isoforms and how these are expressed and differentially regulated in prostate tumours is unknown. Methods: Here we have used RNA-Seq data to globally identify alternative mRNA isoform expression under androgen control in prostate cancer cells, and profiled the expression of these mRNA isoforms in clinical tissue. Results: Our data indicate androgens primarily switch mRNA isoforms through alternative promoter selection. We detected 73 androgen regulated alternative transcription events, including utilisation of 56 androgen-dependent alternative promoters, 13 androgen-regulated alternative splicing events, and selection of 4 androgen-regulated alternative 3' mRNA ends. 64 of these events are novel to this study, and 26 involve previously unannotated isoforms. We validated androgen dependent regulation of 17 alternative isoforms by quantitative PCR in an independent sample set. Some of the identified mRNA isoforms are in genes already implicated in prostate cancer (including LIG4, FDFT1 and RELAXIN), or in genes important in other cancers (e.g. NUP93 and MAT2A). Importantly, analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms (including TPD52, TACC2 and NDUFV3) that are differentially regulated in localised prostate cancer relative to normal tissue, and 3 ( OSBPL1A, CLK3 and TSC22D3) which change significantly with Gleason grade and tumour stage. Conclusions: Our findings dramatically increase the number of known androgen regulated isoforms in prostate cancer, and indicate a highly complex response to androgens in prostate cancer cells that could be clinically important.
Highlights
A single human gene can potentially yield a diverse array of alternative mRNA isoforms, thereby expanding both the repertoire of gene products and subsequently the number of alternative proteins produced. mRNAs with different exon combinations are transcribed from most human genes, and can generate variants that differ in regulatory untranslated regions, or encode proteins with different sub-cellular localisations and functions[1,2,3,4,5]
Global identification of androgen-dependent mRNA isoform production in prostate cancer cells predicts a major role for alternative promoter utilisation We analysed previously published RNAseq data from LNCaP cells[25] to globally profile how frequently androgens drive production of alternative mRNA isoforms in prostate cancer cells. This analysis identified a group of 73 androgen regulated alternative mRNA isoforms, which could be validated by visualisation on the UCSC Genome Browser[45] (Table 1). 64 androgen receptor (AR) regulated mRNA isoforms were novel to this study
The 73 identified mRNA isoforms were generated via androgenregulated utilisation of 56 alternative promoters, 4 alternative 3’ ends and 13 alternative splicing events (Figure 1A)
Summary
A single human gene can potentially yield a diverse array of alternative mRNA isoforms, thereby expanding both the repertoire of gene products and subsequently the number of alternative proteins produced. mRNAs with different exon combinations are transcribed from most (up to 90%) human genes, and can generate variants that differ in regulatory untranslated regions, or encode proteins with different sub-cellular localisations and functions[1,2,3,4,5]. Androgen steroid hormones and the androgen receptor (AR) play a key role in the development and progression of prostate cancer, with alternative splicing enabling cancer cells to produce constitutively active ARs11–13. Androgen binding promotes AR dimerization and its translocation to the nucleus, where it acts as either a transcriptional activator or a transcriptional repressor to dictate prostate specific gene expression patterns[17,18,19,20,21,22,23]. Previous work has shown that androgens can drive the expression of alternative mRNA isoforms as well as transcriptional changes in prostate cancer cells. Methods: Here we have used RNA-Seq data to globally identify alternative mRNA isoform expression under androgen control in prostate cancer cells, and profiled the expression of these mRNA isoforms in clinical tissue. Analysis of transcriptome data from 497 tumour samples in the TGCA prostate adenocarcinoma (PRAD) cohort identified 13 mRNA isoforms
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