lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Yang, L., Lin, C., Jin, C., Yang, J., C., Tanasa, B., Li, W., Merkurjev, D., Ohgi, K., a., Meng, D., Zhang, J., Evans, C., P., & Rosenfeld, M., G. Nature, 500(7464):598-602, Nature Publishing Group, 8, 2013.
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Paper Website abstract bibtex 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.
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title = {lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs.},
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year = {2013},
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keywords = {Animals,Castration,Cell Line, Tumor,Cell Proliferation,Enhancer Elements, Genetic,Enhancer Elements, Genetic: genetics,Humans,Male,Mice,Mice, Nude,Neoplasm Transplantation,Promoter Regions, Genetic,Promoter Regions, Genetic: genetics,Prostatic Neoplasms,Prostatic Neoplasms: genetics,Prostatic Neoplasms: pathology,RNA, Long Noncoding,RNA, Long Noncoding: genetics,Receptors, Androgen,Receptors, Androgen: metabolism,Transcription Factors,Transcription Factors: metabolism,Transcriptional Activation,Transcriptional Activation: genetics,Up-Regulation,Up-Regulation: genetics},
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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 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.},
bibtype = {article},
author = {Yang, Liuqing and Lin, Chunru and Jin, Chunyu and Yang, Joy C and Tanasa, Bogdan and Li, Wenbo and Merkurjev, Daria and Ohgi, Kenneth a and Meng, Da and Zhang, Jie and Evans, Christopher P and Rosenfeld, Michael G},
journal = {Nature},
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