Abstract
Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority1,2. The molecular basis for this clinical heterogeneity remains incompletely understood3,4,5. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer–specific mortality. In vitro and in vivo gain-of-function and loss-of-function experiments indicate that SChLAP1 is critical for cancer cell invasiveness and metastasis. Mechanistically, SChLAP1 antagonizes the genome-wide localization and regulatory functions of the SWI/SNF chromatin-modifying complex. These results suggest that SChLAP1 contributes to the development of lethal cancer at least in part by antagonizing the tumor-suppressive functions of the SWI/SNF complex.
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Acknowledgements
We thank O.A. Balbin, S.A. Tomlins, C. Brenner, S. Deroo and S. Roychowdhury for helpful discussions. This work was supported in part by US National Institutes of Health (NIH) Prostate Specialized Program of Research Excellence grant P50CA69568, Early Detection Research Network grant UO1 CA111275, US NIH grant R01CA132874-01A1 and US Department of Defense grant PC100171 (A.M.C.). A.M.C. is supported by a Doris Duke Charitable Foundation Clinical Scientist Award, by the Prostate Cancer Foundation and by the Howard Hughes Medical Institute. A.M.C. is an American Cancer Society Research Professor. A.M.C. is a Taubman Scholar of the University of Michigan. F.Y.F. was supported by the Prostate Cancer Foundation and by US Department of Defense grant PC094231. Q.C. was supported by US Department of Defense Postdoctoral Fellowship PC094725. J.R.P. was supported by US Department of Defense Predoctoral Fellowship PC094290. M.K.I. was supported by US Department of Defense Predoctoral Fellowship BC100238. A.S. was supported by NIH Predoctoral Fellowship 1F30CA180376-01. J.R.P., M.K.I. and A.S. are Fellows of the University of Michigan Medical Scientist Training Program.
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J.R.P., M.K.I., A.S. and A.M.C. designed the project and directed experimental studies. J.R.P., Q.C., W.C., S.M.D., B.C., S.H., R.M., L.P., T.M. and A.S. performed in vitro studies. X.W. performed in vitro translation assays. I.A.A. and A.S. performed CAM assays. R.B., N.M. and K.J.P. performed in vivo studies. L.P.K. and W.Y. performed histopathological analyses. M.K.I. performed bioinformatics analysis. X.J. and X.C. performed gene expression microarray experiments. J.S. and F.Y.F. facilitated biological sample procurement. F.Y.F. performed clinical analyses. For the Mayo Clinic cohort, R.B.J. provided clinical samples and outcomes data. T.J.T. and E.D. generated and analyzed expression profiles for the Mayo Clinic cohort. E.D., N.E., M.G. and I.A.V. performed statistical analyses of SChLAP1 expression in the Mayo Clinic cohort. J.R.P., M.K.I., A.S. and A.M.C. interpreted data and wrote the manuscript.
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The University of Michigan has filed a patent on lncRNAs in prostate cancer, including SChLAP1, in which A.M.C., J.R.P. and M.K.I. are named as coinventors. Wafergen, Inc., has a non-exclusive license for creating commercial research assays for the detection of lncRNAs, including SChLAP1. GenomeDx Biosciences, Inc., has licensed lncRNAs, including SChLAP1, for the molecular analysis of clinical prostate cancer samples. A.M.C. is a cofounder and advisor of Compendia Biosciences, which supports the Oncomine database. He also serves on the Scientific Advisory Board of Wafergen; Life Technologies and Wafergen had no role in the design or experimentation of this study nor have they participated in the writing of the manuscript. I.A.V., E.D., N.E., M.G. and T.J.T. are employees of GenomeDx Biosciences, Inc.
Supplementary information
Supplementary Text and Figures
Supplementary Note and Supplementary Figures 1–14 (PDF 5101 kb)
Supplementary Table 1
RNA-seq sample information (XLSX 68 kb)
Supplementary Table 2
U-M sample clinical information (XLSX 50 kb)
Supplementary Table 3
Gene correlation signature (XLSX 1286 kb)
Supplementary Table 4
Mayo Clinic sample information (XLSX 49 kb)
Supplementary Table 5
Microarray knockdown results (XLSX 357 kb)
Supplementary Table 6
ChIP-seq results (XLSX 213 kb)
Supplementary Table 7
Primers used (XLSX 12 kb)
Supplementary Table 8
ChIRP probe sequences (XLSX 10 kb)
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Prensner, J., Iyer, M., Sahu, A. et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet 45, 1392–1398 (2013). https://doi.org/10.1038/ng.2771
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DOI: https://doi.org/10.1038/ng.2771
