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 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.
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Liuqing
L
Yang
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chunru
C
Lin
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Chunyu
C
Jin
Department of Urology, School of Medicine, University of California Davis, Sacramento 95817, USA.
Joy C
JC
Yang
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.|Graduate Program, Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla 92037, USA.
Bogdan
B
Tanasa
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Wenbo
W
Li
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.|Bioinformatics and System Biology Program, Department of Bioengineering, University of California San Diego, La Jolla 92093, USA.
Daria
D
Merkurjev
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Kenneth A
KA
Ohgi
Neurosciences Graduate Program, Department of Biological Sciences, University of California San Diego, La Jolla 92093, USA.
Da
D
Meng
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Jie
J
Zhang
Department of Urology, School of Medicine, University of California Davis, Sacramento 95817, USA.
Christopher P
CP
Evans
Howard Hughes Medical Institute, Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Michael G
MG
Rosenfeld
D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*
C416084:PCGEM1 non-coding RNA, human; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen; D014157:Transcription Factors