Widespread and Functional RNA Circularization in Localized Prostate Cancer

Cell. 2019 Feb 7;176(4):831-843.e22. doi: 10.1016/j.cell.2019.01.025.


The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.

Keywords: RNA-seq; biomarker; circular RNA; non-coding RNA; prostate cancer; transcriptome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Profiling / methods
  • Genetic Profile
  • HEK293 Cells
  • Humans
  • Male
  • MicroRNAs / metabolism
  • Prostate / metabolism
  • Prostatic Neoplasms / genetics*
  • RNA / genetics*
  • RNA / metabolism*
  • RNA Splicing / genetics
  • RNA, Circular
  • RNA, Untranslated / genetics
  • Sequence Analysis, RNA / methods
  • Transcriptome


  • MicroRNAs
  • RNA, Circular
  • RNA, Untranslated
  • RNA