title: Methyltransferase inhibitor adenosine dialdehyde suppresses androgen receptor expression and prostate cancer growth.
abstract: OBJECTIVE
  Although most prostate cancers regress after androgen deprivation therapy is given at diagnosis, they eventually regrow in a castration resistant manner, spread systemically and end fatally. Thus, novel therapeutic compounds are needed for prostate cancer. We previously reported that methylation at histone H3 lysine 9 was increased in prostate cancer. In this study we examined the effects of the methyltransferase inhibitor adenosine dialdehyde (Sigma®) on the methylation state of histone H3 lysine 9 and AR gene expression as well as its possible usefulness for prostate cancer.
  
  
  METHODS
  The effect of adenosine dialdehyde on the methylation state of histone H3 lysine 9 and AR gene expression was examined by quantitative real-time polymerase chain reaction and Western blot. We compared methylation at histone H3 lysine 9 at the AR promoter region between androgen dependent and castration resistant prostate cancer by chromatin immunoprecipitation assay. The cytotoxic effect of adenosine dialdehyde on prostate cancer was also evaluated in vitro and in vivo.
  
  
  RESULTS
  Adenosine dialdehyde suppressed the monomethylation and dimethylation of histone H3 lysine 9 and inhibited Twist1 as well as androgen receptor expression, which are critical for the survival and growth of androgen dependent, androgen sensitive and castration resistant prostate cancer cells in which monomethylated histone H3 lysine 9 increased at the 5' untranslated region of the AR gene. As a result, adenosine dialdehyde had a cytotoxic effect on androgen dependent, androgen sensitive and castration resistant prostate cancer cells in vitro. Adenosine dialdehyde also suppressed prostate cancer growth in vivo in a mouse xenograft model.
  
  
  CONCLUSIONS
  Results indicate that the methyltransferase inhibitor adenosine dialdehyde is a promising, novel therapeutic compound for prostate cancer.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Ario
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tatsugami
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000728:Androgens / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; C027579:periodate-oxidized adenosine; D008780:Methyltransferases; D000241:Adenosine