title: The pluripotency factor Nanog is directly upregulated by the androgen receptor in prostate cancer cells.
abstract: BACKGROUND
  The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration-resistance following androgen-deprivation therapy. Thus, identifying and targeting critical AR-regulated genes is one potential method to block castration-resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self-renewal and stem-like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration-resistance.
  
  
  METHODS
  We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP-sequencing data-sets. Nanog over-expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel.
  
  
  RESULTS
  AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75 kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel.
  
  
  CONCLUSIONS
  Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel.
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, Illinois; Department of Surgery, Section of Urology; The University of Chicago, Chicago, Illinois.
authors.forename: Steven
authors.initials: S
authors.lastname: Kregel
authors.forename: Russell Z
authors.initials: RZ
authors.lastname: Szmulewitz
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Vander Griend
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D005786:Gene Expression Regulation / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D000071317:Nanog Homeobox Protein; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D012150:Polymorphism, Restriction Fragment Length; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D001549:Benzamides; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009570:Nitriles; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: NANOGP8; androgen receptor; docetaxel; enzalutamide; nanog; prostate cancer; stem cell