Identification of a novel long non-coding RNA at the 5p15 locus associated with prostate cancer risk

J Panchadsaram1,2, G Tevz1,2, N Stylianou1,2, B Hollier1,2, C Nelson1,2,  The Australian Prostate Cancer Bioresource1, ED Williams1,2, J Clements1,2 and J Batra1,2

  1. Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
  2. Australian Prostate Cancer Research Centre Queensland, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia

Prostate Cancer (PCa) is the second most common cause of cancer death in Australian men. Genome-Wide Association Studies (GWAS) have provided insight into genomic regions that alter an individuals risk of developing PCa and shortlisted 100 risk loci. Through the GWAS, chromosome 5p15 has been identified as a PCa risk associated locus in multi-ethnic populations. IRX4 has been previously identified as the top-ranked expression quantitative trait locus (eQTL) at 5p15. In addition, we discovered a long non-coding RNA (IRX4lncRNA) in the anti-sense strand of IRX4 using paired-end RNAseq. This lncRNA was overexpressed in prostate tumor samples compared to their adjacent non-malignant tissues (n=50). Knockdown of lncRNA reduced proliferation of LNCaP cells, implicating its role in promoting PCa growth. Furthermore, we found an up-regulation of IRX4lncRNA in cells undergoing mesenchymal to epithelial transition, a hallmark of PCa invasion. As androgens promote PCa growth, we tested the effect of androgen ablation therapy on IRX4lncRNA. Surprisingly, it was up-regulated by androgens in VCaP cells and down-regulated in LNCaP cells. Data-mining revealed binding of two crucial transcription factors, AR and ERG, at this locus in VCaP cells, whereas no AR binding was observed in ERG negative LNCaP cells. We also noted a correlation between IRX4lncRNA expression and ERG fusion in our RNA-sequencing data from a cohort of seven androgen-responsive patient-derived xenografts. Further functional characterisation of this novel IRXlncRNA will clarify its therapeutic potential in PCa pathogenesis.