Skip to main content

Thank you for visiting 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.

lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs


Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis1, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells2, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy3. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In ‘resistant’ prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: Signal-dependent interaction between AR and prostate-specific lncRNAs.
Figure 2: Mechanistic study of lncRNA with associated transcription factors/co-activators.
Figure 3: PCGEM1 and PRNCR1 promote hormone-independent activation of the AR transcriptional program in castration-resistant prostate cancer.
Figure 4: Regulation of enhancer–promoter interaction by PRNCR1 and PCGEM1.

Accession codes


Gene Expression Omnibus

Data deposits

The high-throughput sequencing data sets are deposited in the Gene Expression Omnibus database under accession GSE47807.


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

    Article  ADS  CAS  Google Scholar 

  2. Heinlein, C. A. & Chang, C. Androgen receptor in prostate cancer. Endocr. Rev. 25, 276–308 (2004)

    Article  CAS  Google Scholar 

  3. Scher, H. I. & Sawyers, C. L. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J. Clin. Oncol. 23, 8253–8261 (2005)

    Article  CAS  Google Scholar 

  4. Petrovics, G. et al. Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients. Oncogene 23, 605–611 (2004)

    Article  CAS  Google Scholar 

  5. Chung, S. et al. Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility. Cancer Sci. 102, 245–252 (2011)

    Article  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Kypta, R. M. & Waxman, J. Wnt/β-catenin signalling in prostate cancer. Nature Rev. Urology 9, 418–428 (2012)

    Article  CAS  Google Scholar 

  8. Fu, M. et al. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol. Cell. Biol. 23, 8563–8575 (2003)

    Article  CAS  Google Scholar 

  9. Yang, L. et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147, 773–788 (2011)

    Article  CAS  Google Scholar 

  10. Zippo, A. et al. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell 138, 1122–1136 (2009)

    Article  CAS  Google Scholar 

  11. heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009)

    Article  ADS  CAS  Google Scholar 

  12. Hu, R. et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69, 16–22 (2009)

    Article  CAS  Google Scholar 

  13. Sun, A. et al. Adeno-associated virus-delivered short hairpin-structured RNA for androgen receptor gene silencing induces tumor eradication of prostate cancer xenografts in nude mice: a preclinical study. Int. J. Cancer 126, 764–774 (2010)

    Article  CAS  Google Scholar 

  14. Taberlay, P. C. et al. Polycomb-repressed genes have permissive enhancers that initiate reprogramming. Cell 147, 1283–1294 (2011)

    Article  CAS  Google Scholar 

  15. Wang, Q., Carroll, J. S. & Brown, M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol. Cell 19, 631–642 (2005)

    Article  CAS  Google Scholar 

  16. Gu, B. et al. Pygo2 expands mammary progenitor cells by facilitating histone H3 K4 methylation. J. Cell Biol. 185, 811–826 (2009)

    Article  CAS  Google Scholar 

  17. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011)

    Article  CAS  Google Scholar 

  18. Gu, B., Watanabe, K. & Dai, X. Pygo2 regulates histone gene expression and H3 K56 acetylation in human mammary epithelial cells. Cell Cycle 11, 79–87 (2012)

    Article  CAS  Google Scholar 

  19. Lam, M. T. Y. et al. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498, 511–515 (2013)

    Article  ADS  CAS  Google Scholar 

  20. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013)

    Article  ADS  CAS  Google Scholar 

  21. Zhao, J. et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010)

    Article  CAS  Google Scholar 

  22. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  23. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010)

    Article  CAS  Google Scholar 

  24. Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

    Article  CAS  Google Scholar 

  25. Saeed, A. I. et al. TM4 microarray software suite. Methods Enzymol. 411, 134–193 (2006)

    Article  CAS  Google Scholar 

  26. Zang, C. et al. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25, 1952–1958 (2009)

    Article  CAS  Google Scholar 

  27. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010)

    Article  CAS  Google Scholar 

  28. Liu, W. et al. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 466, 508–512 (2010)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  30. Liao, D. F., Monia, B., Dean, N. & Berk, B. C. Protein kinase C-ζ mediates angiotensin II activation of ERK1/2 in vascular smooth muscle cells. J. Biol. Chem. 272, 6146–6150 (1997)

    Article  CAS  Google Scholar 

Download references


We are grateful to X. Dai for providing the PYGO2 shRNA and cDNA constructs and J. Hightower for assistance with figure presentation. This work was supported by National Institutes of Health (NIH) grants DK039949, DK18477, NS034934 and CA173903, Department of Defense grant and initially by a grant from Prostate Cancer Foundation to M.G.R.; by Department of Defense grant PC111467 and SV2C-AACR-DT0812 to C.D.E; by grants from the NIH Pathway to Independence Award (1K99DK094981–01) to C.-R.L.; by US Army Medical Research and Material Command Era of Hope Postdoctoral award (W81XWH-08–1-0554), NIH Pathway to Independence Award (4R00CA166527–02) and Cancer Prevention Research Institute of Texas First-time Faculty Recruitment Award (R1218) to L.-Q.Y.; C.-Y.J. is the recipient of a Cancer Research Institute Postdoctoral Fellowship. M.G.R. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations



L.-Q.Y., C.-R.L. and M.G.R. designed the research, and L.-Q.Y. and C.-R.L. performed most of the experiments, with participation from C.-Y.J.; J.C.Y., under supervision of C.P.E., performed in vivo tumour xenograft experiments. B.T. and D.Mer. performed bioinformatics analyses on GRO-Seq, ChIP-Seq and ChIRP-Seq data. W.-B.L., J.Z. and K.A.O. conducted high-throughput sequencing, and D.Men. helped with ChIRP assays, L.-Q.Y., C.-R.L. and M.G.R. wrote the manuscript.

Corresponding authors

Correspondence to Liuqing Yang, Chunru Lin or Michael G. Rosenfeld.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-19. (PDF 5197 kb)

Supplementary Table 1

This table represents protein identification results for biotinylated lncRNA pulldown. (XLS 42 kb)

Supplementary Table 2

This table shows protein peptides recovered by biotinylated PCGEM1 lncRNA pull down experiments in LNCaP cells. (XLS 105 kb)

Supplementary Table 3

This table shows protein peptides recovered by biotinylated PRNCR1 lncRNA pull down experiments in LNCaP cells. (XLS 144 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yang, L., Lin, C., Jin, C. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer