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

• Published in: Nature (London) Vol. 500; no. 7464; pp. 598 - 602
• Main Authors: Yang, Liuqing, Lin, Chunru, Jin, Chunyu, Yang, Joy C., Tanasa, Bogdan, Li, Wenbo, Merkurjev, Daria, Ohgi, Kenneth A., Meng, Da, Zhang, Jie, Evans, Christopher P., Rosenfeld, Michael G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.08.2013; Nature Publishing Group
• Subjects: 631/337/384/2568; 631/337/572; 631/67; Androgens; Animals; Binding sites; Castration; Cell Line, Tumor; Cell Proliferation; Development and progression; Efficiency; Enhancer Elements, Genetic - genetics; Experiments; Gene expression; Genetic aspects; Genetic regulation; Humanities and Social Sciences; Humans; letter; Male; Mass spectrometry; Mice; Mice, Nude; multidisciplinary; Neoplasm Transplantation; Physiological aspects; Promoter Regions, Genetic - genetics; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Proteins; Receptors, Androgen - metabolism; Recruitment; RNA, Long Noncoding - genetics; Science; Transcription Factors - metabolism; Transcriptional Activation - genetics; Up-Regulation - genetics; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12451

A study of prostate cancer cells reveals a transcriptional activation role for long non-coding RNAs (PRNCR1 and PCGEM1) that bind to the androgen receptor, and is also observed for the truncated androgen receptor characteristic of many aggressive prostate cancers. Cancer growth influenced by long non-coding RNAs Several long non-coding RNAs (lncRNAs) are known to be overexpressed in prostate cancer. Michael Rosenfeld and colleagues have investigated the mechanistic and biological roles of two of these, known as PRNCR1 and PCGEM1. Both are found to interact with the androgen receptor (AR) dependent on specific post-translational modifications, and to enhance the looping of AR-bound enhancers to target gene promoters, leading to enhanced gene expression. They also enhance AR-mediated proliferation in prostate cancer cells and are required for tumour growth in a prostate cancer xenograft mouse model. PRNCR1 and PCGEM1 are upregulated in castration-resistant prostate cancer cell lines. The regulatory roles of lncRNAs in prostate cancer uncovered in this manuscript may open the way to new therapeutic approaches. Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis 1 , 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 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . 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.