RNA editing of androgen receptor gene transcripts in prostate cancer cells.
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.
Martinez
Harryl D
HD
University of California Davis Genome Center, Department of Pharmacology, School of Medicine, University of California, Sacramento, California 95817, USA.
Jasavala
Rohini J
RJ
Hinkson
Izumi
I
Fitzgerald
Latricia D
LD
Trimmer
James S
JS
Kung
Hsing-Jien
HJ
Wright
Michael E
ME
D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D016678:Genome; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017393:RNA Editing; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D017422:Sequence Analysis, DNA
D000728:Androgens; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D008156:Luciferases