title: Valproic acid (VPA) inhibits the epithelial-mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4.
abstract: OBJECTIVE
  The epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. Previous studies have reported that valproic acid (VPA) suppresses prostate carcinoma (PCa) cell metastasis and down-regulates SMAD4 protein levels, which is the key molecule in TGF-β-induced EMT. However, the correlation between VPA and the EMT in PCa remains uncertain.
  
  
  METHODS
  Markers of the EMT in PCa cells and xenografts were molecularly assessed after VPA treatment. The expression and mono-ubiquitination of SMAD4 were also analyzed. After transfection with plasmids that express SMAD4 or short hairpin RNA for SMAD4 down-regulation, markers of EMT were examined to confirm whether VPA inhibits the EMT of PCa cells through the suppression of SMAD4.
  
  
  RESULTS
  VPA induced the increase in E-cadherin (p < 0.05), and the decrease in N-cadherin (p < 0.05) and Vimentin (p < 0.05), in PCa cells and xenografts. SMAD4 mRNA and protein levels were repressed by VPA (p < 0.05), whereas the level of mono-ubiquitinated SMAD4 was increased (p < 0.05). SMAD4 knockdown significantly increased E-cadherin expression in PC3 cells, but SMAD4 over-expression abolished the VPA-mediated EMT-inhibitory effect.
  
  
  CONCLUSIONS
  VPA inhibits the EMT in PCa cells via the inhibition of SMAD4 expression and the mono-ubiquitination of SMAD4. VPA could serve as a promising agent in PCa treatment, with new strategies based on its diverse effects on posttranscriptional regulation.
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Lan
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Chuanwei
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Mao
authors.affiliation: Department of Urology, Dongying People's Hospital, Dongying, 257000, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Yougen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China.
authors.forename: Xunbo
authors.initials: X
authors.lastname: Jin
authors.affiliation: Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China. xqhgege@hotmail.com.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000927:Anticonvulsants; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D014635:Valproic Acid
keywords: Epithelial–mesenchymal transition; Prostate carcinoma; SMAD4; Valproic acid