title: Androgen regulated HN1 leads proteosomal degradation of androgen receptor (AR) and negatively influences AR mediated transactivation in prostate cells.
abstract: We 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 PI3K-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, NKX3.1 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.
authors.affiliation: Department of Bioengineering, Cancer Biology Laboratory, Ege University, Bornova, İzmir, Turkey.
authors.forename: Lokman
authors.initials: L
authors.lastname: Varisli
authors.forename: Ceren
authors.initials: C
authors.lastname: Gonen-Korkmaz
authors.forename: Hamid Muhammad
authors.initials: HM
authors.lastname: Syed
authors.forename: Nuray
authors.initials: N
authors.lastname: Bogurcu
authors.forename: Bilge
authors.initials: B
authors.lastname: Debelec-Butuner
authors.forename: Burcu
authors.initials: B
authors.lastname: Erbaykent-Tepedelen
authors.forename: Kemal Sami
authors.initials: KS
authors.lastname: Korkmaz
mesh_terms: D000728:Androgens / Q000494:pharmacology / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D021381:Protein Transport; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D000728:Androgens; D018797:Cell Cycle Proteins; D005938:Glucocorticoids; C572206:JPT1 protein, human; D007976:Leupeptins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D011944:Receptors, Androgen; D015741:Metribolone; D004958:Estradiol; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D007610:Kallikreins; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde