Abstract A45: GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer

Small non-coding RNAs, such as miRNAs, are implicated in carcinogenesis. To investigate changes in the entire small RNA transcriptome in prostate cancer (PCa) we analyzed 11 clinical sample pools representing different stages of PCa by deep sequencing. We found that most C/D-box small nucleolar RNAs (snoRNAs) are specifically processed to smaller snoRNA-derived RNAs (sdRNAs) highly expressed in PCa. In particular, SNORD78 produces sdRNAs strongly up-regulated in PCa. Together with 9 other snoRNAs, SNORD78 is encoded in the introns of the Growth Arrest Specific 5 gene (GAS5). Examination of SNORD78 and the positioned in a neighboring intron SNORD44 showed that both snoRNAs produce predominantly one sdRNA fragment each, specifically originating from the 39-arm (SNORD78) or the 59-arm (SNORD44) of the precursor sequence. Inspection of the secondary structures of SNORD44 and SNORD78 revealed that they have a degenerated C9/D9 box and can fold in a tight hairpin similarly to miRNAs. In contrast, SNORD74 and SNORD81 that also encoded in introns of GAS5, contain canonical C9/D9 boxes and each produce three equally expressed sdRNAs. Quantitative real time PCR analysis in an independent patient cohort of 106 fresh-frozen clinical samples confirmed the significant up-regulation of all four snoRNAs and their derivative sdRNAs in PCa samples compared to normal tissue. Interestingly, the increased expression of snoRNAs and sdRNAs was not associated with elevated levels of GAS5 transcript. Based on these results, we conclude that (i) separate regulatory mechanisms control the posttranscriptional processing of the spliced GAS5 transcript and the encoded in its introns snoRNAs; (ii) SNORD44, SNORD78, SNORD74 and SNORD81 function as precursors of different sdRNAs; (iii) SNORD44, SNORD78, SNORD74 and SNORD81 and their derivative sdRNAs are significantly up-regulated in PCa and carry biomarker potential for this disease. Citation Format: Elena S. Martens-Uzunova, Anton Kalsbeek, Youri Hoogstrate, Adam Baker, Soren Jensby Nielsen, Tapio Visakorpi, Chris Bangma, Guido Jenster. GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A45.