Format

Send to

Choose Destination
Nature. 2013 Aug 29;500(7464):598-602. doi: 10.1038/nature12451. Epub 2013 Aug 14.

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

Author information

1
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Urology, School of Medicine, University of California Davis, Sacramento 95817, USA.
4
Graduate Program, Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla 92037, USA.
5
Bioinformatics and System Biology Program, Department of Bioengineering, University of California San Diego, La Jolla 92093, USA.
6
Neurosciences Graduate Program, Department of Biological Sciences, University of California San Diego, La Jolla 92093, USA.
#
Contributed equally

Abstract

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, 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 cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. 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.

PMID:
23945587
PMCID:
PMC4034386
DOI:
10.1038/nature12451
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center