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Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation

¹ Urological Diseases Research Center, Department of Urology, Children's Hospital Boston; Department of Surgery, Harvard Medical School; ² Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts; ³ Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York, New York; ⁴ Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois; and ⁵ Department of Biochemistry and Molecular Biology, Louisiana State University Health Science Center, Shreveport, Louisiana

Requests for reprints: Michael R. Freeman, Enders Research Laboratories, Children's Hospital Boston, Suite 1161, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2644; Fax: 617-730-0238; E-mail: michael.freeman{at}childrens.harvard.edu.

Key Words: androgen receptor • prostate cancer • 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. [Cancer Res 2009;69(6):2210–8]

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