Abstract
Abstract Background: Prostate cancer (PC) is the second most common cancer among men. Most PC-related deaths are due to invasive tumors that are treated with therapies inhibiting androgen production or androgen receptor (AR) activity. After an initial response, tumors invariably progress to castration resistant prostate cancers (CRPCs) for which no effective cure exists. Methods and Results: We used transcriptome sequencing to study fresh-frozen tissue specimens from 12 benign prostatic hyperplasias (BPHs), 28 PCs, and 13 CRPCs. Reference-based transcriptome assembly uncovered 145 previously unannotated intergenic PC and CRPC associated long non-coding transcripts (lncRNAs) or isoforms. One third of the transcripts were CRPC-specific. We showed that one of the novel transcripts, Prostate Cancer Associated Transcript 5 (PCAT5), expressed in half of the tumors, was likely regulated by ERG, the key transcription factor in ∼50% of prostate cancers. Genome-wide expression analysis of a PCAT5-positive prostate cancer cell line after PCAT5 knockdown suggested significant alterations in proliferation pathways. In vitro validation of the pathway alterations revealed concordantly dramatic effects in phenotype: stalling of cell growth, migration, invasion, and colony forming potential, and increase in the rate of apoptosis. Conclusions: We identified the key differences between PC and CRPC in transcriptome level, and validated the oncogenic potential of a novel lncRNA in ERG-positive prostate cancers, PCAT5. Our study presents a number of putative lncRNA biomarkers for CRPC, and opportunities for therapeutic intervention. Citation Format: Antti Ylipää, Kati Kivinummi, Matti Annala, Annika Kohvakka, Leena Latonen, Mauro Scaravilli, Kimmo Kartasalo, Simo-Pekka Leppänen, Serdar Karakurt, Janne Seppälä, Olli Yli-Harja, Teuvo L.J. Tammela, Wei Zhang, Tapio Visakorpi, Matti Nykter. Transcriptome sequencing reveals PCAT5 - new ERG-regulated non-coding transcript in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 148. doi:10.1158/1538-7445.AM2015-148
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