title: Nicotinamide inhibits growth of carcinogen induced mouse bladder tumor and human bladder tumor xenograft through up-regulation of RUNX3 and p300.
abstract: OBJECTIVE
  Acetylation of chromatin interacting proteins is central to the epigenetic regulation of gene expression. Various tumor suppressors are inactivated by abnormal epigenetic modification. A great deal of effort has been devoted to developing anticancer agents that reactivate silenced tumor suppressors by modulating chromatin structure. Studies show that histone deacetylase inhibitors can act as anticancer agents and several histone deacetylase inhibitors are currently in clinical trials. We noted that the tumor suppressor RUNX3 is inactivated by promoter hypermethylation in human bladder cancer. We investigated whether reactivation of RUNX3 could suppress bladder cancer development in an animal model.
  
  
  METHODS
  We analyzed RUNX3 reactivation and protein stabilization by a mild inhibitor of class III histone deacetylases, nicotinamide, by immunoprecipitation and immunoblot. Mouse bladder tumor was induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The effect of nicotinamide on Runx3 methylation status and tumor growth was measured.
  
  
  RESULTS
  Nicotinamide induced RUNX3 expression at the transcriptional and posttranslational levels in a carcinogen induced mouse bladder tumor model and in human bladder tumor xenografts. Nicotinamide effectively inhibited the growth and progression of bladder tumors without decreasing body weight.
  
  
  CONCLUSIONS
  Results suggest that nicotinamide has preventive and therapeutic effects on tumorigenesis through multiple mechanisms of RUNX3 expression up-regulation.
authors.affiliation: Institute for Tumor Research and Department of Urology, College of Medicine, Cheongju, South Korea. wjkim@chungbuk.ac.kr
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Changyi
authors.initials: C
authors.lastname: Quan
authors.forename: Hyung-Joon
authors.initials: HJ
authors.lastname: Youn
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Suk-Chul
authors.initials: SC
authors.lastname: Bae
mesh_terms: D000818:Animals; D050677:Core Binding Factor Alpha 3 Subunit / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D051379:Mice; D009536:Niacinamide / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000502:physiology; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; C493730:Runx3 protein, mouse; D009536:Niacinamide; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2