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LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs
While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis(1) yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repert...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034386/ https://www.ncbi.nlm.nih.gov/pubmed/23945587 http://dx.doi.org/10.1038/nature12451 |
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author | 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. |
author_facet | 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. |
author_sort | Yang, Liuqing |
collection | PubMed |
description | While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis(1) yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior 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 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-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 AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors. |
format | Online Article Text |
id | pubmed-4034386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-40343862014-05-27 LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs 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. Nature Article While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis(1) yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior 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 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-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 AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors. 2013-08-14 2013-08-29 /pmc/articles/PMC4034386/ /pubmed/23945587 http://dx.doi.org/10.1038/nature12451 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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. LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title | LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title_full | LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title_fullStr | LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title_full_unstemmed | LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title_short | LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs |
title_sort | lncrna-dependent mechanisms of androgen receptor-regulated gene activation programs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034386/ https://www.ncbi.nlm.nih.gov/pubmed/23945587 http://dx.doi.org/10.1038/nature12451 |
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