A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions.
The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-kappaB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.
Jagla
Monika
M
Faculté de Médecine/Signalisation et Cancer de la Prostate/Equipe d'Accueil 3430, Université Strasbourg, Strasbourg, France.
Fève
Marie
M
Kessler
Pascal
P
Lapouge
Gaëlle
G
Erdmann
Eva
E
Serra
Sebastian
S
Bergerat
Jean-Pierre
JP
Céraline
Jocelyn
J
D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000235:genetics; D005784:Gene Amplification; D014644:Genetic Variation; D000882:Haplorhini; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics*; D015183:Restriction Mapping; D014162:Transfection
D018076:DNA, Complementary; D011944:Receptors, Androgen