TY - JOUR
T1 - LncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs
AU - Yang, Liuqing
AU - Lin, Chunru
AU - Jin, Chunyu
AU - Yang, Joy C.
AU - Tanasa, Bogdan
AU - Li, Wenbo
AU - Merkurjev, Daria
AU - Ohgi, Kenneth A.
AU - Meng, Da
AU - Zhang, Jie
AU - Evans, Christopher P.
AU - Rosenfeld, Michael G.
N1 - Funding Information:
Acknowledgements We are grateful to X. Dai for providing the PYGO2 shRNA and cDNA constructs and J. Hightower for assistance with figure presentation. This work was supported by National Institutes of Health (NIH) grants DK039949, DK18477, NS034934 and CA173903, Department of Defense grant and initially by a grant from Prostate Cancer FoundationtoM.G.R.; byDepartment of Defense grantPC111467 and SV2C-AACR-DT0812toC.D.E;bygrantsfrom the NIHPathway toIndependence Award (1K99DK094981–01) to C.-R.L.; by US Army Medical Research and Material Command Era of Hope Postdoctoral award (W81XWH-08–1-0554), NIH Pathway to Independence Award (4R00CA166527–02) and Cancer Prevention Research Institute of Texas First-time Faculty Recruitment Award (R1218) to L.-Q.Y.; C.-Y.J. is the recipient of a Cancer Research Institute Postdoctoral Fellowship. M.G.R. is an Investigator of the Howard Hughes Medical Institute.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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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U2 - 10.1038/nature12451
DO - 10.1038/nature12451
M3 - Article
C2 - 23945587
AN - SCOPUS:84883132550
SN - 0028-0836
VL - 500
SP - 598
EP - 602
JO - Nature
JF - Nature
IS - 7464
ER -