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Widespread and Functional RNA Circularization in Localized Prostate Cancer

Chen, Sujun, Huang, Vincent, Xu, Xin, Livingstone, Julie, Soares, Fraser, Jeon, Jouhyun, Zeng, Yong, Hua, Junjie Tony, Petricca, Jessica, Guo, Haiyang, Wang, Miranda, Yousif, Fouad, Zhang, Yuzhe, Donmez, Nilgun, Ahmed, Musaddeque, Volik, Stas, Lapuk, Anna, Chua, Melvin L.K., Heisler, Lawrence E., Foucal, Adrien, Fox, Natalie S., Fraser, Michael, Bhandari, Vinayak, Shiah, Yu-Jia, Guan, Jiansheng, Li, Jixi, Orain, Michèle, Picard, Valérie, Hovington, Hélène, Bergeron, Alain, Lacombe, Louis, Fradet, Yves, Têtu, Bernard, Liu, Stanley, Feng, Felix, Wu, Xue, Shao, Yang W., Komor, Malgorzata A., Sahinalp, Cenk, Collins, Colin, Hoogstrate, Youri, de Jong, Mark, Fijneman, Remond J.A., Fei, Teng, Jenster, Guido, van der Kwast, Theodorus, Bristow, Robert G., Boutros, Paul C., He, Housheng Hansen
Cell 2019 v.176 no.4 pp. 831-843.e22
carcinoma, cell growth, cell proliferation, circular RNA, loss-of-function mutation, messenger RNA, metastasis, patients, prostatic neoplasms, screening, sequence analysis, transcriptome, transcriptomics
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.