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Valproic acid (VPA) inhibits the epithelial–mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purposes

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.

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Authors and Affiliations

  1. Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshidong Road, Jinan, 250014, China

    Xiaopeng Lan, Guoliang Lu, Chuanwei Yuan, Shaowei Mao, Yougen Chen, Xunbo Jin & Qinghua Xia

  2. Department of Urology, Dongying People’s Hospital, Dongying, 257000, China

    Wei Jiang

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  1. Xiaopeng Lan
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  2. Guoliang Lu
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  4. Shaowei Mao
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  5. Wei Jiang
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  7. Xunbo Jin
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  8. Qinghua Xia
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Correspondence to Qinghua Xia.

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Lan, X., Lu, G., Yuan, C. et al. Valproic acid (VPA) inhibits the epithelial–mesenchymal transition in prostate carcinoma via the dual suppression of SMAD4. J Cancer Res Clin Oncol 142, 177–185 (2016). https://doi.org/10.1007/s00432-015-2020-4

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  • DOI: https://doi.org/10.1007/s00432-015-2020-4

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