LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

By Liuqing Yang, Chunru Lin, Chunyu Jin, Joy C. Yang, Bogdan Tanasa, Wenbo Li, Daria Merkurjev, K. Ohgi, Da Meng, Jie Zhang and 2 more. Nature, 2013

652 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/305d8c872582ce202e57957991ea6931e12d5ccd

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In Cancer Research

In Molecular Biology

In Pulmonary and Respiratory Medicine

Martin Sauvageau

Citations in the corpus

MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures (2015, neutral): “Input signal [0-19]”
Multiple knockout mouse models reveal lincRNAs are required for life and brain development (2013, background): “Other strategies using RNAi and xenografts to assess the function of lncRNAs in vivo have revealed interesting roles in development and tumor growth (Ulitsky et al., 2011; Wang et al., 2011; Yang et al., 2013).”
Long non-coding RNA (LncRNA) and cancer: a new paradigm (2017, background): “PRNCR1 binds to acetylated androgen receptor (AR) at the enhancer, and recruits histone H3K79 methyltransferase DOT1L (disruptor of telomeric silencing 1-like), which methylates AR that aids in the recruitment of PCGEM1 to the AR N-terminal and modulates target gene expression (35).”