Martinez Harryl D, Jasavala Rohini J, Hinkson Izumi, Fitzgerald Latricia D, Trimmer James S, Kung Hsing-Jien, Wright Michael E
University of California Davis Genome Center, Department of Pharmacology, School of Medicine, University of California, Sacramento, California 95817, USA.
J Biol Chem. 2008 Oct 31;283(44):29938-49. doi: 10.1074/jbc.M800534200. Epub 2008 Aug 14.
Reactivation of the androgen receptor (AR) signaling pathway represents a critical step in the growth and survival of androgen-independent (AI) prostate cancer (CaP). In this study we show the DU145 and PC3 AI human CaP cell lines respond to androgens and require AR expression for optimal proliferation in vitro. Interestingly, AR gene transcripts in DU145 and PC3 cells harbored a large number of single base pair nucleotide transitions that resulted in missense mutations in selected AR codons. The most notable lesion detected in AR gene transcripts included the oncogenic codon 877T-->A gain-of-function mutation. Surprisingly, AR gene transcript nucleotide transitions were not genome-encoded substitutions, but instead the mutations co-localized to putative A-to-I, U-to-C, C-to-U, and G-to-A RNA editing sites, suggesting the lesions were mediated through RNA editing mechanisms. Higher levels of mRNA encoding the A-to-I RNA editing enzymes ADAR1 and ADARB1 were observed in DU145 and PC3 cells relative to the androgen-responsive LNCaP and 22Rv1 human CaP cell lines, which correlated with higher levels of AR gene transcript A-to-I editing detected in DU145 and PC3 cells. Our results suggest that AR gene transcripts are targeted by different RNA editing enzymes in DU145 and PC3 cells. Thus RNA editing of AR gene transcripts may contribute to the etiology of hormone-refractory phenotypes in advanced stage AI CaP.
雄激素受体（AR）信号通路的重新激活是雄激素非依赖性（AI）前列腺癌（CaP）生长和存活的关键步骤。在本研究中，我们发现DU145和PC3这两种AI人CaP细胞系对雄激素有反应，且在体外最佳增殖需要AR表达。有趣的是，DU145和PC3细胞中的AR基因转录本存在大量单碱基对核苷酸转换，导致所选AR密码子出现错义突变。在AR基因转录本中检测到的最显著损伤包括致癌密码子877T→A功能获得性突变。令人惊讶的是，AR基因转录本核苷酸转换并非基因组编码的替代，而是这些突变共定位于假定的A到I、U到C、C到U和G到A的RNA编辑位点，这表明这些损伤是通过RNA编辑机制介导的。相对于雄激素反应性LNCaP和22Rv1人CaP细胞系，在DU145和PC3细胞中观察到编码A到I RNA编辑酶ADAR1和ADARB1的mRNA水平更高，这与在DU145和PC3细胞中检测到的更高水平的AR基因转录本A到I编辑相关。我们的结果表明，DU145和PC3细胞中的AR基因转录本被不同的RNA编辑酶靶向。因此，AR基因转录本的RNA编辑可能促成晚期AI CaP中激素难治性表型的病因。
