Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells

WOS: 000301610000012PubMed ID: 22155408We recently reported that hematological and neurological expressed 1 (HN1) is a ubiquitously expressed, EGF-regulated gene. Expression of HN1 in prostate cell lines down-regulates PI3 K-dependent Akt activation. Here, we investigate whether HN1 is regulated by androgens through the putative androgen response elements (AREs) found in its promoter. Knockdown of HN1 expression by siRNA silencing leads to an increase in Akt((S473)) phosphorylation, resulting in the translocation of androgen receptor (AR) to the nucleus: these effects can be abrogated by the non-specific Akt inhibitor LY294002 but not by the ERK inhibitor PD98059. Furthermore, HN1 overexpression correlates with an increase in ubiquitination-mediated degradation (a consequence of the decrease in S213/210 phosphorylation of AR), ultimately resulting in the down-regulation of AR-mediated expression of the KLK3, KLK4, NKX.1 and STAMP2 genes. We also found that HN1 overexpression suppresses colony formation as well as R1881-mediated growth in LNCaP cells, while it has the opposite effect (increasing colony formation but not proliferation) in PC-3 and DU145 cells. Therefore, we suggest that HN1 maintains a balance between the androgen-regulated nuclear translocation of AR and steady-state Akt phosphorylation, predominantly in the absence of androgens. If so, the balance between cell growth and EGF- and AR-signaling must be tightly regulated by HN1. This work has important implications for prostate cancer research, as AR, EGFR and HN1 are known to be highly expressed in prostate adenocarcinomas. (C) 2011 Elsevier Ireland Ltd. All rights reserved.TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [108S288 (COST_CANGENIN BM0703), 110S134]We would like to thank Prof. Fahri Saatcioglu, Ph.D. (University of Oslo, Institute of Biosciences, Oslo, Norway) for providing the pSG5-AR construct, and the rabbit polyclonal alpha-HN1, and alpha-NKX3.1 antibodies, and FABAL (Ege University, Faculty of Pharmacy, Izmir, Turkey) for technical support in the use of the xCELLigence real-time cell analysis system. This research was supported by Grants 108S288 (COST_CANGENIN BM0703) and 110S134 from TUBITAK to K.S.K