Valproic Acid(VPA)Inhibits The Epithelial-mesenchymal Transition In Prostate Carcinoma Via The Dual Suppression Of SMAD4

BackgroundProstate cancer (PCa) is a male malignant tumor with high incidence and the mortality rate was also ranked in the forefront of malignant tumors. Prostate cancer is easy to metastate.Epithelial-mesenchymal transformation (EMT) of tumor cells play an important rolein invasion and metastasis.In this process, cells lose their epithelial cell properties, and become elongated, resembling interstitial cells and acquiring mesenchymal characters of migration. EMT makes the tumor cells acquire great migration characteristics, resulting in life-threatening tumor metastasis. The molecular mechanism of tumor metastasis had been a major topic in medical research.EMT is thought to be involved in numerous pathways, including TGF-, Notch, Wnt and beta ERK/MAPK. TGF beta signaling in which play an important role. Smad4, the TGF-downstream, is the pathway of information transmission. Smad4 can translocate R-SMADs, which carry information, to the nucleus. Therefore, to further clarify the regulation mechanism is the primary problem. Combined with the previous research, combined with the biological mechanisms of drug and drug research in which can play the role and mechanism of and on the future of the prostate cancer treatment has important significance.ObjectiveThe 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.MethodsMarkers 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 (shRNA) for SMAD4 down-regulation, markers of EMT were examined to confirm whether VPA inhibits the EMT of PCa cells through the suppression of SMAD4.RseultsVPA 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.ConclusionVPA 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 post-transcriptional regulation.