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.