Widespread and Functional RNA Circularization in Localized Prostate Cancer

doi:10.1016/j.cell.2019.01.025

. 2019 Feb 7;176(4):831-843.e22.

doi: 10.1016/j.cell.2019.01.025.

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Sujun Chen¹, Vincent Huang², Xin Xu³, Julie Livingstone², Fraser Soares³, Jouhyun Jeon², Yong Zeng³, Junjie Tony Hua⁴, Jessica Petricca⁴, Haiyang Guo³, Miranda Wang³, Fouad Yousif², Yuzhe Zhang⁵, Nilgun Donmez⁶, Musaddeque Ahmed³, Stas Volik⁶, Anna Lapuk⁶, Melvin L K Chua², Lawrence E Heisler², Adrien Foucal², Natalie S Fox⁷, Michael Fraser⁸, Vinayak Bhandari⁷, Yu-Jia Shiah², Jiansheng Guan⁹, Jixi Li¹⁰, Michèle Orain¹¹, Valérie Picard¹¹, Hélène Hovington¹¹, Alain Bergeron¹¹, Louis Lacombe¹¹, Yves Fradet¹¹, Bernard Têtu¹², Stanley Liu¹³, Felix Feng¹⁴, Xue Wu¹⁵, Yang W Shao¹⁶, Malgorzata A Komor¹⁷, Cenk Sahinalp⁶, Colin Collins¹⁸, Youri Hoogstrate¹⁹, Mark de Jong²⁰, Remond J A Fijneman²¹, Teng Fei²², Guido Jenster¹⁹, Theodorus van der Kwast²³, Robert G Bristow²⁴, Paul C Boutros²⁵, Housheng Hansen He²⁶

Affiliations

¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
² Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Life Sciences, Central China Normal University, Wuhan, Hubei, China; College of Basic Medical Sciences, Dali University, Dali, Yunnan, China.
⁶ Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁸ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Electrical Engineering and Automation, Xiamen University of Technology, Xiamen, China.
¹⁰ State Key Laboratory of Genetic Engineering, Department of Neurology, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
¹¹ Research Centre of CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada.
¹⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada.
¹⁶ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
¹⁷ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Vancouver Prostate Centre, Vancouver, British Columbia, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Urology, Erasmus Medical Centre, Rotterdam, the Netherlands.
²⁰ GenomeScan, Leiden, the Netherlands.
²¹ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
²² College of Life and Health Sciences, Northeastern University, Shenyang, China.
²³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
²⁴ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Manchester Cancer Research Centre, Manchester, UK.
²⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
²⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Electronic address: Hansenhe@uhnresearch.ca.

PMID: 30735634
DOI: 10.1016/j.cell.2019.01.025

Free article

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Sujun Chen et al. Cell. 2019.

Free article

. 2019 Feb 7;176(4):831-843.e22.

doi: 10.1016/j.cell.2019.01.025.

Authors

Affiliations

¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
² Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Life Sciences, Central China Normal University, Wuhan, Hubei, China; College of Basic Medical Sciences, Dali University, Dali, Yunnan, China.
⁶ Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁸ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Electrical Engineering and Automation, Xiamen University of Technology, Xiamen, China.
¹⁰ State Key Laboratory of Genetic Engineering, Department of Neurology, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
¹¹ Research Centre of CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada.
¹⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada.
¹⁶ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
¹⁷ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Vancouver Prostate Centre, Vancouver, British Columbia, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Urology, Erasmus Medical Centre, Rotterdam, the Netherlands.
²⁰ GenomeScan, Leiden, the Netherlands.
²¹ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
²² College of Life and Health Sciences, Northeastern University, Shenyang, China.
²³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
²⁴ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Manchester Cancer Research Centre, Manchester, UK.
²⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
²⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Electronic address: Hansenhe@uhnresearch.ca.

PMID: 30735634
DOI: 10.1016/j.cell.2019.01.025

Abstract

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.

PubMed Disclaimer

Comment in

Coming full circle in cancer.
Burgess DJ. Burgess DJ. Nat Rev Genet. 2019 Apr;20(4):191. doi: 10.1038/s41576-019-0104-8. Nat Rev Genet. 2019. PMID: 30804444 No abstract available.
Implications of the circular RNAs in localized prostate cancer.
Nigam S, Manzar N, Ateeq B. Nigam S, et al. Ann Transl Med. 2019 Sep;7(Suppl 6):S195. doi: 10.21037/atm.2019.07.23. Ann Transl Med. 2019. PMID: 31656774 Free PMC article. No abstract available.

Cited by

Comprehensive scRNA-seq analysis to identify new markers of M2 macrophages for predicting the prognosis of prostate cancer.
Ou Y, Xia C, Ye C, Liu M, Jiang H, Zhu Y, Yang D. Ou Y, et al. Ann Med. 2024 Dec;56(1):2398195. doi: 10.1080/07853890.2024.2398195. Epub 2024 Sep 2. Ann Med. 2024. PMID: 39221762 Free PMC article.
Targeting PLOD2 suppresses invasion and metastatic potential in radiorecurrent prostate cancer.
Frame G, Leong H, Haas R, Huang X, Wright J, Emmenegger U, Downes M, Boutros PC, Kislinger T, Liu SK. Frame G, et al. BJC Rep. 2024;2(1):60. doi: 10.1038/s44276-024-00085-3. Epub 2024 Aug 21. BJC Rep. 2024. PMID: 39184453 Free PMC article.
Proteomic landscape profiling of primary prostate cancer reveals a 16-protein panel for prognosis prediction.
Sun R, A J, Yu H, Wang Y, He M, Tan L, Cheng H, Zhang J, Wang Y, Sun X, Lyu M, Qu M, Huang L, Li Z, Zhang W, Ma K, Dong Z, Ge W, Zhang Y, Ding X, Yang B, Hou J, Xu C, Wang L, Zhu Y, Guo T, Gao X, Yang C. Sun R, et al. Cell Rep Med. 2024 Aug 20;5(8):101679. doi: 10.1016/j.xcrm.2024.101679. Cell Rep Med. 2024. PMID: 39168102 Free PMC article.
The Proteogenomics of Prostate Cancer Radioresistance.
Haas R, Frame G, Khan S, Neilsen BK, Hong BH, Yeo CPX, Yamaguchi TN, Ong EHW, Zhao W, Carlin B, Yeo ELL, Tan KM, Bugh YZ, Zhu C, Hugh-White R, Livingstone J, Poon DJJ, Chu PL, Patel Y, Tao S, Ignatchenko V, Kurganovs NJ, Higgins GS, Downes MR, Loblaw A, Vesprini D, Kishan AU, Chua MLK, Kislinger T, Boutros PC, Liu SK. Haas R, et al. Cancer Res Commun. 2024 Sep 1;4(9):2463-2479. doi: 10.1158/2767-9764.CRC-24-0292. Cancer Res Commun. 2024. PMID: 39166898 Free PMC article.
METTL3-mediated m⁶A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy.
Cheng X, Yang H, Chen Y, Zeng Z, Liu Y, Zhou X, Zhang C, Xie A, Wang G. Cheng X, et al. Cell Mol Biol Lett. 2024 Aug 14;29(1):109. doi: 10.1186/s11658-024-00628-z. Cell Mol Biol Lett. 2024. PMID: 39143552 Free PMC article.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- H1 Connect
- The Lens - Patent Citations
Medical
- MedlinePlus Health Information
Research Materials
- Addgene Non-profit plasmid repository
Miscellaneous
- SciCrunch

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Affiliations

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Authors

Affiliations

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous