Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of SChLAP1 as a prostate cancer–associated lncRNA.
Figure 2: SChLAP1 expression characterizes aggressive prostate cancer.
Figure 3: SChLAP1 coordinates cancer cell invasion in vitro and metastatic seeding in vivo.
Figure 4: SChLAP1 antagonizes SNF5 function and attenuates SNF5 genome-wide localization.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

NCBI Reference Sequence

Referenced accessions

Gene Expression Omnibus

References

  1. Etzioni, R., Cha, R., Feuer, E.J. & Davidov, O. Asymptomatic incidence and duration of prostate cancer. Am. J. Epidemiol. 148, 775–785 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Cooperberg, M.R., Moul, J.W. & Carroll, P.R. The changing face of prostate cancer. J. Clin. Oncol. 23, 8146–8151 (2005).

    Article  PubMed  Google Scholar 

  3. Grasso, C.S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Prensner, J.R., Rubin, M.A., Wei, J.T. & Chinnaiyan, A.M. Beyond PSA: the next generation of prostate cancer biomarkers. Sci. Transl. Med. 4, 127rv3 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Taylor, B.S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Berger, M.F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Prensner, J.R. & Chinnaiyan, A.M. The emergence of lncRNAs in cancer biology. Cancer Discov. 1, 391–407 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsai, M.C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kotake, Y. et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene. Oncogene 30, 1956–1962 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Prensner, J.R. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu, J. et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell 17, 443–454 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rhodes, D.R. et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166–180 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Glinsky, G.V., Glinskii, A.B., Stephenson, A.J., Hoffman, R.M. & Gerald, W.L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Setlur, S.R. et al. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J. Natl. Cancer Inst. 100, 815–825 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Nakagawa, T. et al. A tissue biomarker panel predicting systemic progression after PSA recurrence post-definitive prostate cancer therapy. PLoS ONE 3, e2318 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Asangani, I.A. et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol. Cell 49, 80–93 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Tusher, V.G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shen, H. et al. The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer. Cancer Res. 68, 10154–10162 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roberts, C.W. & Orkin, S.H. The SWI/SNF complex—chromatin and cancer. Nat. Rev. Cancer 4, 133–142 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Reisman, D., Glaros, S. & Thompson, E.A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Sun, A. et al. Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers. Prostate 67, 203–213 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Dechassa, M.L. et al. Architecture of the SWI/SNF-nucleosome complex. Mol. Cell. Biol. 28, 6010–6021 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 22, 1775–1789 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De, S. et al. Dynamic BRG1 recruitment during T helper differentiation and activation reveals distal regulatory elements. Mol. Cell. Biol. 31, 1512–1527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Euskirchen, G.M. et al. Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches. PLoS Genet. 7, e1002008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yen, K., Vinayachandran, V., Batta, K., Koerber, R.T. & Pugh, B.F. Genome-wide nucleosome specificity and directionality of chromatin remodelers. Cell 149, 1461–1473 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Cline, M.S. et al. Integration of biological networks and gene expression data using Cytoscape. Nat. Protoc. 2, 2366–2382 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Arredouani, M.S. et al. Identification of the transcription factor single-minded homologue 2 as a potential biomarker and immunotherapy target in prostate cancer. Clin. Cancer Res. 15, 5794–5802 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Holzbeierlein, J. et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am. J. Pathol. 164, 217–227 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl. Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. LaTulippe, E. et al. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res. 62, 4499–4506 (2002).

    CAS  PubMed  Google Scholar 

  41. Luo, J.H. et al. Gene expression analysis of prostate cancers. Mol. Carcinog. 33, 25–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Vanaja, D.K., Cheville, J.C., Iturria, S.J. & Young, C.Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  43. Varambally, S. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8, 393–406 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Wallace, T.A. et al. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 68, 927–936 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Yu, Y.P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Rubin, M.A. et al. Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clin. Cancer Res. 6, 1038–1045 (2000).

    CAS  PubMed  Google Scholar 

  47. Tomlins, S.A. et al. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 10, 177–188 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chu, C., Qu, K., Zhong, F.L., Artandi, S.E. & Chang, H.Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol. Cell 44, 667–678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maher, C.A. et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl. Acad. Sci. USA 106, 12353–12358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Levin, J.Z. et al. Comprehensive comparative analysis of strand-specific RNA sequencing methods. Nat. Methods 7, 709–715 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Feng, J., Liu, T. & Zhang, Y. Using MACS to identify peaks from ChIP-Seq data. Curr. Protoc. Bioinformatics Chapter 2 Unit 2.14 (2011).

  54. Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Shin, H., Liu, T., Manrai, A.K. & Liu, X.S. CEAS: cis-regulatory element annotation system. Bioinformatics 25, 2605–2606 (2009).

    CAS  PubMed  Google Scholar 

  56. Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kannan, K. et al. Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing. Proc. Natl. Acad. Sci. USA 108, 9172–9177 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pflueger, D. et al. Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res. 21, 56–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Trapnell, C., Pachter, L. & Salzberg, S.L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hulsen, T., de Vlieg, J. & Alkema, W. BioVenn—a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics 9, 488 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Karnes, R.J. et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J. Urol. 10.1016/j.juro.2013.06.017 (11 June 2013).

  62. Blute, M.L., Bergstralh, E.J., Iocca, A., Scherer, B. & Zincke, H. Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J. Urol. 165, 119–125 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Vergara, I.A. et al. Genomic “dark matter” in prostate cancer: exploring the clinical utility of ncRNA as biomarkers. Front. Genet. 3, 23 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Arul M Chinnaiyan.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2771

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing