Histone deacetylase inhibitor valproic acid (VPA) promotes the epithelial mesenchymal transition of colorectal cancer cells via up regulation of Snail.

Abstract

Histone deacetylase inhibitors (HDACIs) have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in colorectal cancer (CRC) cells. Our present study revealed that one HDAC inhibitor, valproic acid (VPA), can obviously promote in vitro motility of HCT-116 and SW480 cells. VPA treatment significantly down regulates the expression of epithelial markers E-Cadherin (E-Cad) and Zona occludin-1(ZO-1) while up regulates the mesenchymal markers Vimentin (Vim) and N-cadherin (N-Cad), suggesting that VPA can trigger the epithelial-mesenchymal transition (EMT) of CRC cells. VPA treatment significantly increases the expression and nuclear localization of Snail, the key transcription factors of EMT. Snail knockdown by siRNAs obviously reverses VPA induced EMT of HCT-116 and SW480 cells. Further, VPA can decrease the ubiquitination, increase the acetylation, and then elevate the stabilization of Snail. VPA also increases the phosphorylation of Akt/GSK-3β. The inhibitor of PI3K/Akt, LY2994002, significantly attenuates VPA induced phosphorylation of Akt and GSK-3β and up regulation of Snail and Vim. Collectively, our data reveal that VPA can trigger the EMT of CRC cells via up regulation of Snail through AKT/GSK-3β signals and post-transcriptional modification. It suggests that more attention should be paid when VPA used as a new anticancer drug for CRC patients.

• Authors: Jutao Feng, Junhua Cen, Jun Li, Rujin Zhao, Canhua Zhu, Zongxin Wang, Jiafen Xie, Wei Tang
• Journal: Cell adhesion & migration (Cell Adh Migr) Vol. 9 Issue 6 Pg. 495-501 ( 2015) ISSN: 1933-6926 [Electronic] United States
• PMID: 26632346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Snail Family Transcription Factors
• Transcription Factors
• Valproic Acid
• Phosphatidylinositol 3-Kinases
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Cell Movement (genetics)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 (genetics)
• Glycogen Synthase Kinase 3 beta
• HCT116 Cells
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Phosphatidylinositol 3-Kinases (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Signal Transduction
• Snail Family Transcription Factors
• Transcription Factors (biosynthesis, genetics)
• Valproic Acid (administration & dosage)