IncRNA-dependent mechanisms of androgen-receptor - regulated gene activation programs

摘要

几个“长的非编码RNAs”(IncRNAs)已知在前rn列腺癌中过度表达。Michael Rosenfeld及同事rn研究了这些“长的非编码RNAs”中的两个的机rn制功能和生物功能，它们分别是PRNCRl和rnPCGEMl。二者都被发现依赖于特定的翻译后rn修饰与雄性激素受体(AR)发生相互作用，增rn强与AR结合在一起的增强子向目标基因启动rn子的成环作用(looping)，导致基因表达增强。rn它们还增强前列腺癌细胞由AR-介导的增殖，rn并且是一个前列腺癌异种移植小鼠模型的肿瘤rn生长所需要的。PRNCR1和PCGEM1在“去势rn抵抗性前列腺癌”细胞系中被上调。这篇文章rn中所揭示的IncRNAs在前列腺癌中的调控作用rn也许能为新的治疗方法开辟道路。%Although recent studies have indicated roles of long non-coding RNAs (IncRNAs) 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 IncRNAs 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 IncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM 1-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 IncRNAs 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 IncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed IncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.