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

Nature volume 500, pages 598–602 (2013)Cite this article

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Abstract

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.

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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.

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Accession codes

Accessions

Gene Expression Omnibus

Data deposits

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

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Acknowledgements

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

Author notes

  1. Liuqing Yang and Chunru Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Howard Hughes Medical Institute, University of California San Diego, La Jolla, 92093, California, USA

    Liuqing Yang, Chunru Lin, Chunyu Jin, Bogdan Tanasa, Wenbo Li, Daria Merkurjev, Kenneth A. Ohgi, Jie Zhang & Michael G. Rosenfeld

  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Liuqing Yang & Chunru Lin

  3. Department of Urology, School of Medicine, University of California Davis, Sacramento, 95817, California, USA

    Joy C. Yang & Christopher P. Evans

  4. Graduate Program, Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Bogdan Tanasa

  5. Department of Bioengineering, Bioinformatics and System Biology Program, University of California San Diego, La Jolla, 92093, California, USA

    Daria Merkurjev

  6. Department of Biological Sciences, Neurosciences Graduate Program, University of California San Diego, La Jolla, 92093, California, USA

    Da Meng

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Contributions

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.

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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)

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Yang, L., Lin, C., Jin, C. et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 500, 598–602 (2013). https://doi.org/10.1038/nature12451

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