title: TRPM2 mediates histone deacetylase inhibition-induced apoptosis in bladder cancer cells.
abstract: OBJECTIVE
  Inhibition of histone deacetylase (HDAC) activity results in growth arrest and apoptosis in multiple types of cancer cells. It has been well established that p21 is responsible for HDAC inhibitor (HDACi)-induced growth inhibition, while the mechanism underlying HDACi-elicited apoptosis in bladder cancer cells remains largely unknown.
  
  
  METHODS
  In this study, the apoptotic response to HDACi (trichostatin A and sodium butyrate) with different concentrations was determined by flow cytometry analysis and real-time polymerase chain reaction was conducted to examine the TRPM2 (Transient receptor potential cation channel, subfamily M, member 2) expression change on HDACi treatment. TRPM2 knockdown and overexpression were performed to investigate the role of TRPM2 in HDACi-induced apoptosis. The mechanism of HDACi-elicited upregulation of TRPM2 was studied by chromatin-immunoprecipitation.
  
  
  RESULTS
  HDACi efficiently induced cell apoptosis and TRPM2 upregulation in a time- and dose-dependent manner in T24 bladder cancer cells. Functional analysis revealed that TRPM2 overexpression promotes apoptosis of T24 cells. Conversely, TRPM2 depletion remarkably antagonized HDACi-induced apoptosis. Furthermore, HDAC inhibition-elicited TRPM2 upregulation is caused by the increase of acetylated H3K9 (H3K9Ac) enrichment in TRPM2 promoter.
  
  
  CONCLUSIONS
  These data suggest that the HDACi-elicited upregulation of TRPM2 expression is required for HDACi-induced apoptosis in bladder cancer cells and that HDACi activated the enrichment of H3K9Ac-represented permissive chromatin in TRPM2 promoter.
authors.affiliation: Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China .
authors.forename: Qi-feng
authors.initials: QF
authors.lastname: Cao
authors.forename: Su-bo
authors.initials: SB
authors.lastname: Qian
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Wei-ming
authors.initials: WM
authors.lastname: Wang
authors.forename: Hai-bo
authors.initials: HB
authors.lastname: Shen
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D020148:Butyric Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D020148:Butyric Acid; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: HDAC inhibitor; TRPM2; apoptosis; bladder cancer