Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression

Abstract

High-throughput sequencing of polyA+ RNA (RNA-Seq) in human cancer shows remarkable potential to identify both novel markers of disease and uncharacterized aspects of tumor biology, particularly non-coding RNA (ncRNA) species. We employed RNA-Seq on a cohort of 102 prostate tissues and cells lines and performed ab initio transcriptome assembly to discover unannotated ncRNAs. We nominated 121 such Prostate Cancer Associated Transcripts (PCATs) with cancer-specific expression patterns. Among these, we characterized PCAT-1 as a novel prostate-specific regulator of cell proliferation and target of the Polycomb Repressive Complex 2 (PRC2). We further found that high PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1-repressed target genes. Taken together, the findings presented herein identify PCAT-1 as a novel transcriptional repressor implicated in subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes.

Retracted: Long noncoding RNA MALAT1 enhances the docetaxel resistance of prostate cancer cells via miR‐145‐5p‐mediated regulation of AKAP12

“…Emerging studies suggest that lncRNAs are involved in the progression of PCa. PCAT‐1, transcribed from the introns of known genes which correlate with the differentiation degree of PCa, was identified as a prostate‐specific regulator of cell proliferation 15. Prostate cancer antigen 3 (PCA3), also known as differential display 3 (DD3), has been thoroughly explored as a PCa‐specific biomarker 16.…”

Linc00963: A novel, long non-coding RNA involved in the transition of prostate cancer from androgen-dependence to androgen-independence

“…Emerging evidence indicates that LncRNAs which are RNA specis >200 bp in length (9) and frequently polyadenylated (10), are involved in physiological aspects of cell-type determination and tissue homeostasis (11), and in cancer lncRNAs are known to play important roles in carcinogenesis and tumor progression (12)(13)(14)(15)(16). One of the overexpressed lncRNAs in prostate cancer, PCGEM1, is tissue specific and PCa-associated lncRNA gene (15), whereas another highly expressed lncRNA, PRNCR1 (PCAT8), is pervasively transcribed from the critical region of 8q24 Region 2, which is significantly associated with PCa susceptibility (17).…”

“…Previous studies also demonstrated that a novel long non-coding RNA (named PlncRNA-1) was frequently overexpressed in PCa cell lines and tissues and associated with cell viability and cell apoptosis (18). Recent studies have revealed the contribution of other lncRNAs as proto-oncogenes, drivers of metastatic transformation and tumor suppressor genes in prostate cancer, such as prostate cancer gene 3 (PCA3), metastasis associated in lung adenocarcinoma transcript 1 (MALAT-1), and PCAT-1 (13,(19)(20)(21). However, the global expression profile of lncRNAs in androgen-dependent (AD) to androgen-independent (AI) prostate cancer is not fully uncovered.…”

Macro lncRNAs

“…The HOTAIR ncRNA was the prototype lincRNA in humans and was shown to have a role in regulating repressive chromatin at the HOXD gene cluster and in modulating the cancer epigenome, 17,18 however this function may not be conserved in mice. 19 Many thousands of lincRNAs have now been identified, [20][21][22][23][24][25] that mostly appear to cis-acting silencer, i.e., the macro lncRNA, on the maternal allele. The Airn macro lncRNA silences the Igf2r imprinted gene cluster.…”

“…The approach of ab initio reconstruction of the transcriptome based on identifying transcription islands and connecting them by split-mapped reads, has allowed the detection of many thousands of novel spliced lncRNAs. 22,25,67 Bioinformatic pipelines have been developed including programs such as Scripture, 22 Cufflinks 78 and the split-mapper TopHat, 79 which greatly increased the numbers and reliability of detected lncRNAs. The spliced nature of lncRNAs thus increases confidence in identifying novel transcripts but a bioinformatic pipeline to detect macro lncRNAs in RNA-seq data are lacking.…”