Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation.
The regulation of androgen receptor (AR) expression in prostate cancer is still poorly understood. The activation of the epidermal growth factor receptor (EGFR) in prostate cancer cells was previously shown to lower AR expression by a rapamycin-sensitive, posttranscriptional mechanism involving the AR mRNA 5'-untranslated region (5'-UTR). In a search for an intermediate within the EGFR/phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway that regulates AR at this site, we identified the nucleic acid-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNP-K), by mass spectrometric analysis of Akt immune complexes from lipid raft-enriched subcellular fractions. We show here that hnRNP-K is a novel inhibitor of AR mRNA translation that regulates androgen-responsive gene expression and prostate cancer cell proliferation. A functional hnRNP-K binding site involved in down-regulating AR protein levels was identified in the AR mRNA 5'-UTR. Further analysis revealed that hnRNP-K is also able to inhibit AR translation in the absence of the 5'-UTR, consistent with the presence of additional predicted hnRNP-K binding sites within the AR open reading frame and in the 3'-UTR. Immunohistochemical analysis of a human prostate cancer tissue microarray revealed an inverse correlation between hnRNP-K expression and AR protein levels in organ-confined prostate tumors and a substantial decline in cytoplasmic hnRNP-K in metastases, despite an overall increase in hnRNP-K levels in metastatic tumors. These data suggest that translational inhibition of AR by hnRNP-K may occur in organ-confined tumors but possibly at a reduced level in metastases. HnRNP-K is the first protein identified that directly interacts with and regulates the AR translational apparatus.
Mukhopadhyay
Nishit K
NK
Urological Diseases Research Center, Department of Urology, Children's Hospital Boston, Boston, MA 02115, USA.
Kim
Jayoung
J
Cinar
Bekir
B
Ramachandran
Aruna
A
Hager
Martin H
MH
Di Vizio
Dolores
D
Adam
Rosalyn M
RM
Rubin
Mark A
MA
Raychaudhuri
Pradip
P
De Benedetti
Arrigo
A
Freeman
Michael R
MR
D059002:Androgen Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics
D059002:Androgen Receptor Antagonists; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D012333:RNA, Messenger; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen