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Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression

Abstract

Noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease and to reveal uncharacterized aspects of tumor biology. Here we discover 121 unannotated prostate cancer–associated ncRNA transcripts (PCATs) by ab initio assembly of high-throughput sequencing of polyA+ RNA (RNA-Seq) from a cohort of 102 prostate tissues and cells lines. We characterized one ncRNA, PCAT-1, as a prostate-specific regulator of cell proliferation and show that it is a target of the Polycomb Repressive Complex 2 (PRC2). We further found that patterns of PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1–repressed target genes. Taken together, our findings suggest that PCAT-1 is a transcriptional repressor implicated in a subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes.

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Figure 1: Analysis of transcriptome data for the detection of unannotated transcripts.
Figure 2: Prostate cancer transcriptome sequencing reveals dysregulation of unannotated transcripts.
Figure 3: Unannotated intergenic transcripts differentiate prostate cancer and benign prostate samples.
Figure 4: PCAT-1 is a marker of aggressive cancer and a PRC2-repressed ncRNA.
Figure 5: PCAT-1 promotes cell proliferation.
Figure 6: Prostate cancer tissues recapitulate PCAT-1 signaling.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

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Acknowledgements

We thank K. Ramnarayanan and R. Morey for technical assistance with next generation sequencing. We thank R.J. Lonigro, S. Kaylana-Sundaram, T. Barrette, and M. Quist for help with sequencing data analysis, and R. Mehra, B. Han and K. Suleman for prostate tissue specimens. We thank C. Trapnell and G. Pertea for assistance with computational analyses. We thank S. Tomlins, Y.-M. Wu, S. Roychowdhury and members of the Chinnaiyan laboratory for advice and discussions. We thank R. Beroukhim for guidance. This work was supported in part by the US National Institutes of Health (NIH) Prostate Specialized Program of Research Excellence grant P50CA69568, the Early Detection Research Network grant UO1 CA111275 (to A.M.C.), the NIH R01CA132874-01A1 (to A.M.C.), the Department of Defense grant W81XWH-10-0652 and W81XWH-11-1-0337 (to A.M.C.) and the National Center for Functional Genomics supported by the Department of Defense (to A.M.C.). A.M.C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Award, a Burroughs Wellcome Foundation Award in Clinical Translational Research and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society Research Professor. N.P. was supported by a University of Michigan Prostate SPORE Career Development Award. C.A.M. was supported by the American Association of Cancer Research Amgen Fellowship in Clinical/Translational Research, the Canary Foundation and American Cancer Society Early Detection Postdoctoral Fellowship, and a Prostate Cancer Foundation Young Investigator Award. Q.C. was supported by a Department of Defense Postdoctoral Fellowship grant PC094725. J.R.P. was supported by the NIH Cancer Biology Training grant CA009676-18 and the Department of Defense Predoctoral Fellowship W81XWH-10-1-0551. M.K.I. was supported by the Department of Defense Predoctoral Fellowship W81XWH-11-1-0136. J.R.P. and M.K.I. are Fellows of the University of Michigan Medical Scientist Training Program.

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M.K.I., J.R.P. and A.M.C. designed the project and directed experimental studies. M.K.I., O.A.B., C.S.G. and C.A.M. developed computational platforms and performed sequencing data analysis. M.K.I., O.A.B. and H.K.I. performed statistical analyses. J.R.P., S.M.D., J.C.B., Q.C., N.P., H.D.K., B.L., X.W., I.A.A., X.C., X.J. and D.R. performed experimental studies. J.S. and J.T.W. coordinated biospecimens. M.K.I., J.R.P. and A.M.C. interpreted data and wrote the manuscript.

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Correspondence to Arul M Chinnaiyan.

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Competing interests

The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which A.M.C. is a co-inventor. The diagnostic field of use for ETS gene fusions has been licensed to GenProbe Inc. The University of Michigan has a sponsored research agreement with GenProbe, which is unrelated to this study. GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript.

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Prensner, J., Iyer, M., Balbin, O. et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 29, 742–749 (2011). https://doi.org/10.1038/nbt.1914

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