Abstract
Prostate Cancer (CaP) is the second leading cause of cancer related death in USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5'-untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of prostate tumors. Here we have investigated the unique cellular transcriptome associated with over-expression of ERG in ERG-inducible LNCaP cell model system of human CaP. Comprehensive transcriptome analyses reveal a distinct signature that distinguishes ERG dependent and independent CaP in LNCaP cells. Our data highlight a significant heterogeneity among the transcripts. Out of the 526 statistically significant differentially expressed genes, 232 genes are up-regulated and 294 genes are down-regulated in response to ERG. These ERG-associated genes are linked to several major cellular pathways, cell cycle regulation being the most significant. Consistently our data indicate that ERG plays a key role in modulating the expression of genes required for G1 to S phase transition, particularly those that affect cell cycle arrest at G1 phase. Moreover, cell cycle arrest in response to ERG appears to be promoted by induction of p21 in a p53 independent manner. These findings may provide new insights into mechanisms that promote growth and progression of CaP.
Highlights
Prostate cancer (CaP) is the most commonly diagnosed male malignancy and a leading cause of cancer related deaths in USA [1,2,3]
To identify the gene signature associated with over-expression of ETS-related genes (ERG) and to gain insight into the Transmembrane Protease Serine2 (TMPRSS2)-ERG gene fusion, we performed RNA sequencing (RNA-seq) analysis
We have identified a total of 526 statistically significant differentially expressed genes (DEGs) in ERG+ cells compared to ERG- LnTE3 cells (Supplementary Data 1)
Summary
Prostate cancer (CaP) is the most commonly diagnosed male malignancy and a leading cause of cancer related deaths in USA [1,2,3]. ERG is the most commonly overexpressed oncogene in CaP [5] and arises from a fusion between androgen receptor regulated promoter of TMPRSS2 and ETS-related genes (ERG) [6]. Various studies have reported that 50% of radical prostatectomy samples have a fusion of the TMPRSS2 with the coding sequences of ERG [7]. Subsequent studies established that the variability in the frequency of TMPRSS2:ERG fusion gene ranges from 27% to 79% [8]. There is a tremendous interest in dissecting the molecular mechanism by which the TMPRSS2-ERG fusion promote progression of CaP [9]. The discovery of the TMPRSS2:ERG gene fusion shifts the current paradigm in cancer genomics from experimental to bioinformatics approaches [7].
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