title: Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer.
abstract: Zinc finger E-box-binding protein 2 (ZEB2) is known to help mediate the epithelial-to-mesenchymal transition, and thereby it facilitates cancer metastasis. This study was initiated to explore whether ZEB2 expression differs in prostate cancer (PCa, n=7) and benign prostatic hyperplasia (BPH, n=7) tissues. In PCa tissues, the levels of both immunoreactive ZEB2 and androgen receptor (AR) were found to be significantly higher (P<0.05) when compared with BPH tissues. Co-regulation of AR and ZEB2 prompted us to investigate the role of androgenic stimuli in ZEB2 expression. ZEB2 expression was found to be significantly (P<0.05) upregulated after androgen stimulation and downregulated following AR silencing in LNCaP cells, an androgen-dependent PCa cell line. This finding suggested AR as a positive regulator of ZEB2 expression in androgen-dependent cells. Paradoxically, androgen-independent (AI) cell lines PC3 and DU145, known to possess low AR levels, showed significantly (P<0.05) higher expression of ZEB2 compared with LNCaP cells. Furthermore, forced expression of AR in PC3 (PC3-AR) and DU145 (DU-AR) cells led to reductions in ZEB2 expression, invasiveness, and migration. These cells also exhibited an increase in the levels of E-cadherin (a transcriptional target of ZEB2). Co-transfection of AR and ZEB2 cDNA constructs prevented the decline in invasiveness and migration to a significant extent. Additionally, ZEB2 downregulation was associated with an increase in miR200a/miR200b levels in PC3-AR cells and with a decrease in miR200a/miR200b levels in AR-silenced LNCaP cells. Thus, AR acts as a positive regulator of ZEB2 expression in androgen-dependent cells and as a negative regulator in AI PCa cells.
authors.affiliation: Primate Biology Laboratory, National Institute for Research in Reproductive Health (NIRRH), Indian Council of Medical Research, JM Street, Parel, Mumbai 400012, India GS Medical College and KEM Hospital, Parel, Mumbai 400012, India The Centre for Medical Bioinformatics, NIRRH, Parel, Mumbai 400012, India Department of Pathology, Tata Memorial Hospital, Mumbai 400012, India.
authors.forename: Sheeba
authors.initials: S
authors.lastname: Jacob
authors.forename: S
authors.initials: S
authors.lastname: Nayak
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Fernandes
authors.forename: R S
authors.initials: RS
authors.lastname: Barai
authors.forename: S
authors.initials: S
authors.lastname: Menon
authors.forename: U K
authors.initials: UK
authors.lastname: Chaudhari
authors.forename: S D
authors.initials: SD
authors.lastname: Kholkute
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Sachdeva
mesh_terms: D000728:Androgens / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: C410798:AR protein, human; D000728:Androgens; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D013196:Dihydrotestosterone
keywords: EMT; ZEB2; androgen receptor; prostate cancer