title: Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer.
abstract: BACKGROUND
  Polycomb repressive complex 2 (PRC2) mediates gene silencing through histone H3K27 methylation. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 3-Dezaneplanocin-A (DZNeP) is an inhibitor of PRC2 with broad anticancer activity.
  
  
  METHODS
  we investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145).
  
  
  RESULTS
  Exploring GEO and Oncomine databases, we found that specific PRC2 genes (EED, EZH2, SUZ12) predict poor prognosis in PC. Non-toxic DZNeP concentrations completely eradicated LNCaP and DU145 prostatosphere formation, and significantly reduced the expression of CSC markers. At comparable doses, other epigenetic drugs were not able to eradicate CSCs. DZNeP was also able to reduce PC cell invasion. Cells pre-treated with DZNeP were significantly less tumorigenic (LNCaP) and formed smaller tumors (DU145) in immunocompromised mice.
  
  
  CONCLUSIONS
  DZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.
authors.affiliation: Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Crea
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hurt
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Mathews
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cabarcas
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins